Stimulus-triggered prodrugs

ABSTRACT

Set forth herein, inter alia, are compositions and methods for treating diseases with prodrugs. Provided herein are prodrug compositions for inhibiting the function of proteins, compositions and methods for treating diseases associated with oxidative compounds, oxidatively-sensitive prodrugs of inhibitors of metalloproteases. and methods of inhibiting metalloproteases using oxidatively-sensitive prodrugs.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication 61/357,477, filed Jun. 22, 2010, which is herebyincorporated by reference in its entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant R01HL00049-01 awarded by the National Institute of Health. The Governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Many therapeutics used to treat diseases, for example cancer, infectiousdiseases, inflammatory diseases, exhibit toxicity or confer undesirableside effects at doses that limit the amount of the therapeutic that canbe safely administered and therefore limit the benefit provided by suchtherapeutics. It would be preferable if such drugs could be administeredin a prodrug form that masked the inherent toxicity of the compoundsfrom healthy tissues, and yet released the fully active drug species atthe desired site of action. Such a technology would have the potentialto increase the therapeutic window of a variety of drugs, possiblyallowing them to be used safely at a more efficacious dose, and withreduced incidence of undesired side-effects for the patient. The use ofprodrugs to confer improved properties such as increased bioavailabilityor aqueous solubility is a well established concept in the art ofpharmaceutical research.

Matrix metalloproteinases (MMPs) are a ubiquitous class ofzinc(II)-dependent hydrolytic enzymes that have been associated with awide range of pathologies including cancer, arthritis, heart disease,and stroke.¹⁻³ Clinical trials of matrix metalloproteinase inhibitors(MMPi) have frequently been hampered by the onset of musculoskeletalsyndrome (MSS), which manifests as severe joint pain, and has beenattributed to non-specific, systemic inhibition of MMPs and othermetalloenzymes.^(4,5)

Provided herein are compositions and methods that address these andother problems in the art.

BRIEF SUMMARY OF THE INVENTION

In a first aspect, a method of treating a disease in a patient in needof such treatment is provided. The method includes administering atherapeutically effective amount of an oxidatively-sensitive prodrug tothe patient. In an embodiment, the oxidatively-sensitive prodrugincludes a drug moiety covalently linked to an oxidatively-sensitiveprodrug moiety. In one embodiment, the drug moiety includes a moietyknown to be useful for treating the disease for which the prodrug isadministered (e.g. the drug moiety is capable of forming a drug known tobe useful for treating the disease for which the prodrug isadministered).

In a second aspect, a method of inhibiting the activity of ametalloprotein is provided. In one embodiment, the method includescontacting the metalloprotein with a metal binding moiety formed fromthe reaction of an oxidatively-sensitive prodrug and a reactive oxygenspecies.

In a third aspect, a compound is provided having the formula:

Within formula (I), (Ia), (II), (III), (IIIa) and (IV), A, B, C, and Dare independently a drug moiety. L¹ is a bond or unsubstituted alkylene.X¹ is —NH— or —O—. R¹ is independently —B(OH)₂, an ROS-reactive boronicester, hydrogen, halogen, —CN, —SR^(13B), —SO₂Cl, —SO₃H, —SO₄H,—SO₂NR^(7B)R^(8B), —NHNH₂, —ONR^(7B)R^(8B), —NHC═(O)NHNH₂,—NHC═(O)NR^(7B)R^(8B), —N(O)_(m), —NR^(7B)R^(8B), —C(O)R^(9B),—C(O)—OR^(10B), —C(O)NR^(11B)R^(12B), —OR^(13B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, peptidyl, or peptidomimetic moiety.

R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), and R^(13B) areindependently hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, peptidyl or peptidomimeticmoiety.

R² is independently hydrogen, halogen, —CN, —SR^(13B), —SO₂Cl, —SO₃H,—SO₄H, —SO₂NR^(7B)R^(8B), —NHNH₂, —ONR^(7B)R^(8B), —NHC═(O)NHNH₂,—NHC═(O)NR^(7B)R^(8B), —N(O)_(m), —NR^(7B)R^(8B), —C(O)R^(9B),—C(O)—OR^(10B), C(O)NR^(11B)R^(12B), —OR^(13B), substituted orunsubstituted alkyl (e.g. methyl), substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, an electron withdrawing group,peptidyl, or peptidomimetic moiety. The symbol z is an integer from 0 to5. The symbol m is an integer from 1 to 2.

In another aspect, is a compound having the formula

E is a drug moiety. L² is independently a bond, —O—, —S—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. R⁶ is asubstituted or unsubstituted carbohydrate moiety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Structures of inhibitors and proinhibitors tested in this study.Compounds include the ZBGs (examples of potential zinc binding drugs)1-hydroxy-pyridin-2(1H)-one (1), 3-hydroxy-2-methyl-4-pyrone (3) and3-hydroxy-2-methyl-4-pyrothione (5) as well as the full-length MMPi1,2-HOPO-2 (7).

FIG. 2. Absorption spectra of the glucose-protected ZBG 2 (example of apotential prodrug comprising a carbohydrate moiety) (0.05 mM, HEPESbuffer, pH=7.5) in the presence of β-glucosidase (16 U) monitored overtime. The heavy lines are the initial (dashed) and final (solid) spectraand arrows indicate the change in spectra over time. The spectrum of anauthentic sample of ZBG 1 (dotted) is also shown.

FIG. 3. Absorption spectra of the glucose-protected ZBG 4 (0.06 mM inHEPES buffer) in the presence of β-glucosidase (16 U) monitored everyminute for one hour with spectra shown every 2 min. The heavy lines arethe initial (dashed) and final (solid) spectra; arrows indicate changein spectra over time. An authentic sample of the ZBG (compound 3, ˜0.1mM) in HEPES buffer is also shown.

FIG. 4. Absorption spectra of the glucose-protected ZBG 6 (0.05 mM inHEPES buffer) in the presence of β-glucosidase (16 U) monitored everyminute for one hour with spectra shown every 2 min. The heavy lines arethe initial (dashed) and final (solid) spectra; arrows indicate changein spectra over time. An authentic sample of the ZBG (compound 5, ˜0.1mM) in HEPES buffer is also shown (light gray solid line).

FIG. 5. HPLC traces of compounds 1 (bottom) and 2 (middle) and compound2 after incubation with β-glucosidase (50 U, top) for 1 h. Retentiontimes are 4.92 min for 1 and 4.42 min for 2.

FIG. 6. HPLC traces of compounds 3 (bottom) and 4 (middle) and compound4 after incubation with β-glucosidase (50 U, top) for 1 h. Retentiontimes are 6.84 min for 3 and 5.07 min for 4.

FIG. 7. HPLC traces of compounds 5 (bottom) and 6 (middle) and compound6 after incubation with β-glucosidase (50 U, top) for 1 h. Retentiontimes are 11.21 min for 5 and 6.60 min for 6.

FIG. 8. Absorption spectra of the glucose-protected full-lengthinhibitor 1,2-HOPO-2 (8) (0.05 mM in HEPES buffer) in the presence ofβ-glucosidase (100 U) at 37° C. monitored every 5 min for 4 h withspectra shown every 10 min. The heavy lines are the initial (dashed) andfinal (solid) spectra; arrows indicate change in spectra over time. Asample of 1,2-HOPO-2 (7) (˜0.05 mM) in HEPES buffer is also shown (lightgray solid line).

FIG. 9. HPLC traces of compound 8 (0.8 mM) over time in the presence ofβ-glucosidase (250 U). Retention times are 12.88 min for 8 and 19.39 minfor the product 7.

FIG. 10. Lineweaver-Burk plot of the initial velocity of β-glucosidase(100 U) cleavage with varying amounts of inhibitor 8. A K_(m) of ˜210 μMwas obtained.

FIG. 11. Top: Absorption spectra of the glucose-protected full-lengthinhibitor 8 (0.05 mM) in 0.1 M HCl monitored every hour for 24 h(overlapping solid spectra). A sample of 8 (˜0.05 mM) in HEPES buffer isalso shown (dashed). The overlapping spectra indicate that compound 8 isstable to hydrolysis in the presence of acid. Bottom: Percent inhibitionof MMP-8 with compounds 7 and 8 tested at 150 nM in the absence andpresence of β-glucosidase. Results represent the average of twoindependent experiments run each in duplicate.

FIG. 12. Percent inhibition of MMP-9 with compounds 1-8 tested at 1 mMfor 1 and 2, 4 mM for 3 and 4, 125 μM for 5 and 6, and 16 μM for 7 and8, in the absence (white) and presence (black) of β-glucosidase.

FIG. 13. ZBGs and their sulfonate ester derivatives (PZBGs) (examples ofpotential oxidatively sensitive prodrugs and potential zinc bindingmoieties) examined in this study.

FIG. 14. Analysis of PZBGs in the presence of H₂O₂. Top. PZBG-1a andZBG-1. Middle. Absorption spectra of PZBG-1a (0.05 mM, 50 mM HEPESbuffer, pH=7.5) in the presence of H₂O₂ (0.9 mM, 18 equiv) monitoredevery 5 min for 60 min. The dashed line represents the initial spectrum,and an authentic sample of ZBG-1 is shown as a heavy line. The arrowsindicate change in spectra over time. Bottom. HPLC chromatogram ofPZBG-1a, PZBG-1a+H₂O₂, and ZBG-1. Retention times are 11.5 min forPZBG-1a and 5.0 min for ZBG-1.

FIG. 15. Absorption spectra (Top to Bottom) of PZBG-2a, PZBG-3a, andPZBG-4-a, respectively (0.05 mM, 50 mM HEPES buffer, pH=7.5) in thepresence of H₂O₂ (0.9 mM, 18 equiv) monitored every 5 min for 60 min.The overlapping spectra indicate that no cleavage of the protectinggroup is occurring in the presence of H₂O₂.

FIG. 16. Top panel: Scheme 1. Activation of proinhibitor PZBG-5a orPZBG-5b with H₂O₂ results in generation of the inhibitor 1,2-HOPO-2. Incontrast, treatment of proinhibitor PZBG-6a with H₂O₂ did not result inproduction of the inhibitor PY-2. Bottom panel: Absorption spectra ofPZBG-5b (0.05 mM, 50 mM HEPES buffer, pH=7.5) in the presence of H₂O₂(0.9 mM, 18 equiv excess) monitored every 5 min for 60 min. The dashedline represents the initial spectrum, and an authentic sample of1,2-HOPO-2 is shown as a heavy line. The arrows indicate change inspectra over time.

FIG. 17. Percent inhibition of MMP-12 with proinhibitors PZBG-5a,PZBG-5b, and PZBG-6a tested at 50 nM in the absence (gray) and presence(black) of H₂O₂ after 30 min of activation.

FIG. 18. Boronic Ester Protecting Strategy. A novel, self-immolativeapproach to the development of ROS-activated, boronic esterproinhibitors (oxidatively sensitive prodrugs comprising ROS-reactiveboronic esters and metal binding moieties) (Top) has been discovered.The synthesis of protected B19 with a self-immolative linker and boronicester trigger (Middle). UV-Visible spectroscopy (Bottom) shows cleanconversion of B19 to ZBG1 upon exposure to H₂O₂.

FIG. 19. Three approaches to the development of ROS-activated boronicester proMMPi demonstrated with the methyl salicylate derivatives B1-B3using either an ether or ester linked self-immolative linker or throughdirect linkage of the protecting group.

FIG. 20. Methyl salicylate derivatives B4-B9 investigated in this studywith varying leaving groups and linkage strategies.

FIG. 21. Absorption spectra of B1 (50 μM in HEPES buffer, pH 7.5) in thepresence of H₂O₂ (18 eq) monitored every 2 min over 60 min. The dashedline is the starting spectrum and the bold solid line is the finalspectrum. A sample of methyl salicylate is shown as a dotted line. Thearrow represents the change in absorption over time.

FIG. 22. Table 2. Pseudo first-order rate constants calculated with anexcess of H₂O₂.

FIG. 23. Protected MBGs (prochelators) (potential oxidatively sensitiveprodrugs comprising metal binding moieties) designed with a benzyl-etherself-immolative linker.

FIG. 24. Absorption spectra of B2 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (18 eq) monitored every minute for 30 min.The dashed line is the initial spectra and the bold solid line is thefinal spectra; the arrow indicates the change in spectra over time. Anauthentic sample of methyl 2-hydroxybenzoate (0.05 mM in HEPES buffer(50 mM, pH 7.5)) is shown as a dotted line.

FIG. 25. Top. Absorption spectra of B3 (0.05 mM in HEPES buffer (50 mM,pH 7.5)) in the presence of H₂O₂ (18 eq) monitored every minute for 1 hrwith spectra shown every 2 min. The dashed line is the initial spectraand the bold solid line is the final spectra; the arrow indicates thechange in spectra over time. Bottom. Absorption spectra of B3 (0.05 mMin HEPES buffer (50 mM, pH 7.5)) in the presence of H₂O₂ (180 eq)monitored every minute for 1 hr with spectra shown every 2 min. Thedashed line is the initial spectra and the bold solid line is the finalspectra; the arrow indicates the change in spectra over time. Anauthentic sample of methyl 2-hydroxybenzoate (0.05 mM in HEPES buffer(50 mM, pH 7.5)) is shown as a dotted line.

FIG. 26. Top. HPLC traces of compounds methyl salicylate, B1 andcompound B1 after reaction with H₂O₂ (1.8 eq) for 30 min. Bottom. Zoomedin view of chromatograms. Retention times are 14.2 min for methylsalicylate and 14.5 min for B1.

FIG. 27. Top. HPLC traces of compounds methyl salicylate, B2 andcompound B2 after reaction with H₂O₂ (1.8 eq) for 30 min. Bottom. Zoomedin view of chromatograms. Retention times are 14.2 min for methylsalicylate and 13.9 min for B2.

FIG. 28. HPLC traces of compounds methyl salicylate, B3, and compound B3after reaction with H₂O₂ (18 eq) for 30 min, 60 min and 120 min.Retention times are 14.2 min for methyl salicylate and 8.7 min for B3.

FIG. 29. Absorption spectra of B4 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for 30min. The dashed line is the initial spectra and the bold solid line isthe final spectra. An authentic sample of methyl 2-mercaptobenzoate(0.05 mM in HEPES buffer (50 mM, pH 7.5)) is shown as a dotted line. Theoverlapping spectra indicate there is no cleavage of the protectinggroup in the presence of H₂O₂.

FIG. 30. Absorption spectra of B5 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for 1h. The dashed line is the initial spectra and the bold solid line is thefinal spectra. An authentic sample of methyl 2-aminobenzoate (0.05 mM inHEPES buffer (50 mM, pH 7.5)) is shown as a dotted line. The minimalchange in spectra over time indicates that there is no formation of2-aminobenzoate in the presence of H₂O₂.

FIG. 31. Absorption spectra of B6 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for 1h. The dashed line is the initial spectra and the bold solid line is thefinal spectra. An authentic sample of methyl 4-aminobenzoate (0.05 mM inHEPES buffer (50 mM, pH 7.5)) is shown as a dotted line. The minimalchange in spectra over time indicates that there is no formation of4-aminobenzoate in the presence of H₂O₂.

FIG. 32. Top. Absorption spectra of B7 (0.05 mM in HEPES buffer (50 mM,pH 7.5)) in the presence of H₂O₂ (18 eq) monitored every minute for 30min. The dashed line (hidden) is the initial spectra and the bold solidline is the final spectra. An authentic sample of4-(aminomethyl)benzoate (0.05 mM in HEPES buffer (50 mM, pH 7.5)) isshown as a dotted line. The overlapping spectra indicate there is nocleavage of the protecting group in the presence of H₂O₂. Bottom. HPLCtraces of compounds 4-(aminomethyl)benzoate, B7 and compound B7 afterreaction with H₂O₂ (22 eq) for 30 min. Retention times are 5.8 min for4-(aminomethyl)benzoate and 8.6 min for B7.

FIG. 33. HPLC traces of compounds methyl 4-aminobenzoate, B6 andcompound B6 after reaction with H₂O₂ (22 eq) for 30 min. Retention timesare 10.2 min for methyl 4-aminobenzoate, 14.5 min for B6, and 14.3 forB6 after reaction with H₂O₂. LC-MS(+) gave an m/z peak at 258.1confirming the release of the boronic ester to the phenolic moiety.

FIG. 34. Absorption spectra of B8 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for 50min. The dashed line is the initial spectra and the bold solid line isthe final spectra. An authentic sample of 4-(aminomethyl)benzoate (0.05mM in HEPES buffer (50 mM, pH 7.5)) is shown as a dotted line.

FIG. 35. Top. Absorption spectra of B9 (0.05 mM in HEPES buffer (50 mM,pH 7.5)) in the presence of H₂O₂ (18 eq) monitored every minute for 30min. The dashed line is the initial spectra and the bold solid line isthe final spectra. An authentic sample of 4-(aminomethyl)benzoate (0.05mM in HEPES buffer (50 mM, pH 7.5)) is shown as a dotted line. Bottom.HPLC traces of compounds 2-(aminomethyl)benzoate with H₂O₂ (22 eq), B9and B9 after reaction with H₂O₂ (22 eq) for 30 min. Retention times are6.3 min and 9.1 min for 2-(aminomethyl)benzoate and 13.9 min for B9.

FIG. 36. Top. Absorption spectra of B10 (0.05 mM in HEPES buffer (50 mM,pH 7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for30 min. The dashed line is the initial spectra and the bold solid lineis the final spectra. An authentic sample of maltol (0.05 mM in HEPESbuffer (50 mM, pH 7.5)) is shown as a dotted line. Bottom. HPLC tracesof compounds maltol, B10 and B10 after reaction with H₂O₂ (1.8 eq) for30 min. Retention times are 6.8 min for maltol and 10.8 min for B10.

FIG. 37. Top. Absorption spectra of B11 (0.05 mM in HEPES buffer (50 mM,pH 7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for30 min. The dashed line is the initial spectra and the bold solid lineis the final spectra. An authentic sample of 1,2-HOPO (0.05 mM in HEPESbuffer (50 mM, pH 7.5)) is shown as a dotted line. Bottom. HPLC tracesof compounds 1,2-HOPO, B11 and B11 after reaction with H₂O₂ (1.8 eq) for30 min. Retention times are 4.9 min for 1,2-HOPO and 10.8 min for B11.

FIG. 38. Absorption spectra of B12 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for 1hr. The dashed line is the initial spectra and the bold solid line isthe final spectra. An authentic sample of 3,4-HOPO (0.05 mM in HEPESbuffer (50 mM, pH 7.5)) is shown as a dotted line; the arrows indicatethe change in absorption over time.

FIG. 39. Absorption spectra of B13 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (5 eq) monitored every two minutes for 1hr. The dashed line is the initial spectra and the bold solid line isthe final spectra. An authentic sample of tropolone (0.05 mM in HEPESbuffer (50 mM, pH 7.5)) is shown as a dotted line; the arrow indicatesthe change in absorption over time.

FIG. 40. Absorption spectra of B14 (0.05 mM in HEPES buffer (50 mM, pH7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for 1hr. The dashed line is the initial spectra and the bold solid line isthe final spectra. An authentic sample of 8-hydroxy quinoline (0.05 mMin HEPES buffer (50 mM, pH 7.5)) is shown as a dotted line; the arrowindicates the change in absorption over time.

FIG. 41. Top. Absorption spectra of B15 (0.05 mM in HEPES buffer (50 mM,pH 7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for1 hr. The dashed line is the initial spectra and the bold solid line isthe final spectra. The minimal change in spectra over time indicatesthat there is no formation of the MBG in the presence of H₂O₂. Bottom.HPLC traces of compounds N-(quinolin-8-yl)methanesulfonamide, B15 andB15 after reaction with H₂O₂ (18 eq) for 30 min. Retention times are10.9 min for N-(quinolin-8-yl)methanesulfonamide, 10.7 min for B15, and9.9 min and 11.0 min for B15 with H₂O₂. LC-MS(+) shows an m/z peak of329.1 at 9.9 min indicative of cleavage of the boronic ester to thephenolic moiety.

FIG. 42. Top. Absorption spectra of B16 (0.05 mM in HEPES buffer (50 mM,pH 7.5)) in the presence of H₂O₂ (18 eq) monitored every two minutes for1 hr. The dashed line is the initial spectra and the bold solid line isthe final spectra. An authentic sample of N-hydroxybenzamide (0.05 mM inHEPES buffer (50 mM, pH 7.5)) is shown as a dotted line. The minimalchange in spectra over time indicates that there is no formation of theMBG in the presence of H₂O₂. Bottom. HPLC traces of compoundsN-hydroxybenzamide, B16 and B16 after reaction with H₂O₂ (18 eq) for 2.5h. Retention times are 6.1 min for N-hydroxybenzamide, 11.2 min for B16,and 10.9 min for B16 with H₂O₂. LC-MS(+) shows an m/z peak of 266.1([M+Na]⁺) at 10.9 min indicative of cleavage of the boronic ester to thephenolic moiety.

FIG. 43. Release of the active inhibitor 1,2-HOPO-2 in the presence ofH₂O₂ through a self-immolative linker strategy.

FIG. 44. Structures of proinhibitors B17 and B18 and their activeinhibitors 1,2-HOPO-2 and PY-2, respectively, and the protected B19-B21.

FIG. 45. IC₅₀ values of proinhibitors and inhibitors against MMP-9 andMMP-12 as measured using a fluorescence based assay. Data are theaverage of two experiments.

FIG. 46. Percent inhibition of MMP-9 and MMP-12 with proinhibitors B17and B18 tested at 10 μM for MMP-9 and 50 nM for MMP-12 in the absenceand presence of 100 μM H₂O₂ after one hour of activation. Data are theaverage of four experiments.

FIG. 47. Absorption spectra of the protected ZBG B19 (0.05 mM in HEPESbuffer) in the presence of H₂O₂ (0.90 mM) monitored every 2 min for 40min. The initial spectra is represented by a dashed line and anauthentic sample of the ZBG, 2-hydroxypyridine-1-oxide, is shown inlight gray; arrows indicate change in spectra over time.

FIG. 48. Absorption spectra of the protected ZBG B20 (0.05 mM in HEPESbuffer) in the presence of H₂O₂ (0.90 mM) monitored every 2 min for 40min. The initial spectra is represented by a dashed line and anauthentic sample of the ZBG, 3-hydroxy-2-methyl-4H-pyran-4-one (maltol),is shown in light gray; arrows indicate change in spectra over time.

FIG. 49. Absorption spectra of the protected ZBG B21 (0.05 mM in HEPESbuffer) in the presence of H₂O₂ (0.90 mM) monitored every 2 min for 40min. The initial spectra is represented by a dashed line and anauthentic sample of the ZBG, 3-hydroxy-2-methyl-4H-pyran-4-one (maltol),is shown in light gray; arrows indicate change in spectra over time.

FIG. 50. Absorption spectra of benzyl protected control molecules (0.05mM in HEPES buffer) in the presence of H₂O₂ (0.90 mM) monitored every 5min for 60 min. The initial spectra of each compound is shown as adashed line. The overlapping spectra indicate that no cleavage of theprotecting group is occurring in the presence of H₂O₂.

FIG. 51. Absorption spectra of protected ZBGs B19 and B20 (0.05 mM inHEPES, A and B, respectively) in the presence of KO₂ (0.10 mM) andcatalase (5U). Spectra were monitored every 3 min for 60 min. Theinitial spectra of each is shown as a dashed line. The overlappingspectra indicate that compounds B19 and B20 are stable towards KO₂.

FIG. 52. Absorption spectra of the protected ZBGs at 50 μM in HEPESbuffer (B19, panel A; B20, panel B; B21, panel C) monitored over 24 h.Overlapping spectra of compounds B19 and B20 indicate their stabilitytowards hydrolysis while compound B21 shows significant hydrolysis inbuffer. The initial spectra of each compound is shown in the dashed lineand the final spectra after 24 h is shown for B21 in light gray.

FIG. 53. Absorbance spectra of proinhibitor B17 (0.05 mM in HEPESbuffer) in the presence of H₂O₂ (0.90 mM) monitored every 2 min for 1 h.The initial spectra is represented by the dashed line and an authenticsample of 1,2-HOPO-2 is represented by the light gray line; arrowsindicate change in spectra over time.

FIG. 54. Absorbance spectra of proinhibitor B18 (0.05 mM in HEPESbuffer) in the presence of H₂O₂ (0.90 mM) monitored every 2 min for 1 h.The initial spectra is represented by the dashed line and an authenticsample of PY-2 is represented by the light gray line; arrows indicatechange in spectra over time.

DETAILED DESCRIPTION I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “or” as used herein should in general be construednon-exclusively. For example, an embodiment of “a formulation includingA or B” would typically present an aspect with a formulation includingboth A and B. “Or” should, however, be construed to exclude thoseaspects presented that cannot be combined without contradiction.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e., C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude, but are not limited to, groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl,homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl,n-octyl, and the like. An unsaturated alkyl group is one having one ormore double bonds or triple bonds. Examples of unsaturated alkyl groupsinclude, but are not limited to, vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. An alkoxy is an alkyl attached to the remainder of the moleculevia an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, consisting of at least one carbon atom and atleast one heteroatom selected from the group consisting of B, O, N, P,Si, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) B, O, N, P, S, and Si may be placed at any interiorposition of the heteroalkyl group or at the position at which the alkylgroup is attached to the remainder of the molecule. Examples include,but are not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,and the like. Examples of heterocycloalkyl include, but are not limitedto, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as B, N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is an alkyl group as defined above. R′ mayhave a specified number of carbons (e.g., “C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, boronic esters, boronic acids, —OR′, ═O, ═NR′,═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NRSO₂R′, —NR′NR″R′″, —ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, peptidyl,and peptidomimetic moiety, in a number ranging from zero to (2 m′+1),where m′ is the total number of carbon atoms in such radical. R, R′, R″,R′″, and R″″ each preferably independently refer to hydrogen,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, peptidyl, and peptidomimetic moiety, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′, R″, R′″, and R″″ are preferably independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ groups when more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T—C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, boron (B), oxygen (O), nitrogen (N), sulfur (S), phosphorus(P), and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

(A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, oxo, halogen, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl,peptidyl, peptidomimetic moiety, and(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, substituted with at least one substituent selected from:

-   -   (i) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted        alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, peptidyl, and peptidomimetic moiety,        and    -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (a) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen,            unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, peptidyl, and            peptidomimetic moiety, and        -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            or heteroaryl, substituted with at least one substituent            selected from: oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂,            halogen, boronic acid, boronic ester, unsubstituted alkyl,            unsubstituted heteroalkyl, unsubstituted cycloalkyl,            unsubstituted heterocycloalkyl, unsubstituted aryl, and            unsubstituted heteroaryl, peptidyl, and peptidomimetic            moiety, and    -   (iii) boronic acid and boronic ester;        (C) boronic acid and boronic ester.

A “boronic acid”, as used herein, means a substituent with the structure—B(OH)₂.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₄-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. Alternatively, at least one or all of these groupsare substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, and/or each substituted or unsubstituted heterocycloalkyl isa substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, and/or each substituted or unsubstitutedheterocycloalkylene is a substituted or unsubstituted 3 to 8 memberedheterocycloalkylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and/or each substitutedor unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to7 membered heterocycloalkyl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₅-C₇cycloalkylene, and/or each substituted or unsubstitutedheterocycloalkylene is a substituted or unsubstituted 5 to 7 memberedheterocycloalkylene. In some embodiments, the compound is a chemicalspecies set forth in the Examples section below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

A “prodrug,” as used herein, refers to an inactive pharmacologicalsubstance that becomes active upon undergoing a chemical reaction (e.g.metabolization in vivo, bioactivation, enzymatic reaction) or a lessactive pharmacological substance that becomes more active uponundergoing a chemical reaction. A produg includes a prodrug moiety and adrug moiety (e.g. a metal binding moiety such as a zinc binding moiety).A “prodrug moiety,” is a portion of a prodrug that is modified orremoved (either partially or wholly) when the prodrug undergoes thechemical reaction (including enzymatic reaction) thereby producing anactive drug. The presence of a prodrug moiety is responsible for theinactivity, or reduced activity, of the prodrug. Likewise, the “drugmoiety” is a portion of the prodrug that forms, in combination with achemical moiety (e.g. —OH, or —NH₂) produced from the modification orremoval of the prodrug moiety, a drug. A “drug” is an activepharmacological substance (e,g, any chemical substance, includingorganic molecules and inorganic molecules and combinations thereof,useful in the treatment, cure, or prevention of a disease or condition,or used to otherwise enhance the physical or mental well-being of anorganism, such as a human). As used herein, the term “drug”, “medicine”,and “medication” are interchangeable.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C— or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

The terms “peptide,” “polypeptide,” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues.

The term “peptidyl” and “peptidyl moiety” means a monovalent peptide.

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs. Naturally occurring amino acidsare those encoded by the genetic code, as well as those amino acids thatare later modified, e.g., hydroxyproline, γ-carboxyglutamate, andO-phosphoserine. Amino acid analogs refers to compounds that have thesame basic chemical structure as a naturally occurring amino acid, i.e.,an α-carbon that is bound to a hydrogen, a carboxyl group, an aminogroup, and an R group, e.g., homoserine, norleucine, methioninesulfoxide, methionine methyl sulfonium. Such analogs have modified Rgroups (e.g., norleucine) or modified peptide backbones, but retain thesame basic chemical structure as a naturally occurring amino acid. Aminoacid mimetics refers to chemical compounds that have a structure that isdifferent from the general chemical structure of an amino acid, but thatfunctions in a manner similar to a naturally occurring amino acid. Anoligomer comprising amino acid mimetics is a peptidomimetic. Apeptidomimetic moiety is a monovalent peptidomimetic.

Amino acids may be referred to herein by either their commonly knownthree letter symbols or by the one-letter symbols recommended by theIUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise,may be referred to by their commonly accepted single-letter codes.

An amino acid or nucleotide base “position” is denoted by a number thatsequentially identifies each amino acid (or nucleotide base) in thereference sequence based on its position relative to the N-terminus (or5′-end). Due to deletions, insertions, truncations, fusions, and thelike that must be taken into account when determining an optimalalignment, in general the amino acid residue number in a test sequencedetermined by simply counting from the N-terminus will not necessarilybe the same as the number of its corresponding position in the referencesequence. For example, in a case where a variant has a deletion relativeto an aligned reference sequence, there will be no amino acid in thevariant that corresponds to a position in the reference sequence at thesite of deletion. Where there is an insertion in an aligned referencesequence, that insertion will not correspond to a numbered amino acidposition in the reference sequence. In the case of truncations orfusions there can be stretches of amino acids in either the reference oraligned sequence that do not correspond to any amino acid in thecorresponding sequence.

The terms “numbered with reference to” or “corresponding to,” when usedin the context of the numbering of a given amino acid or polynucleotidesequence, refers to the numbering of the residues of a specifiedreference sequence when the given amino acid or polynucleotide sequenceis compared to the reference sequence.

A “conservative substitution” as used with respect to amino acids,refers to the substitution of an amino acid with a chemically similaramino acid. Amino acid substitutions which often preserve the structuraland/or functional properties of the polypeptide in which thesubstitution is made are known in the art and are described, forexample, by H. Neurath and R. L. Hill, 1979, in “The Proteins,” AcademicPress, New York. The most commonly occurring exchanges areisoleucine/valine, tyrosine/phenylalanine, aspartic acid/glutamic acid,lysine/arginine, methionine/leucine, aspartic acid/asparagine, glutamicacid/glutamine, leucine/isoleucine, methionine/isoleucine,threonine/serine, tryptophan/phenylalanine, tyrosine/histidine,tyrosine/tryptophan, glutamine/arginine, histidine/asparagine,histidine/glutamine, lysine/asparagine, lysine/glutamine,lysine/glutamic acid, phenylalanine/leucine, phenylalanine/methionine,serine/alanine, serine/asparagine, valine/leucine, andvaline/methionine. The following eight groups each contain amino acidsthat are conservative substitutions for one another: 1) Alanine (A),Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N),Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine(L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y),Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C),Methionine (M) (see, e.g., Creighton, Proteins (1984)). In someembodiments, there may be at least 1, at least 2, at least 3, at least4, at least 5, at least 6, at least 7, at least 8, at least 9, at least10, at least 15, at least 20, at least 25, at least 30, at least 35, orat least 40 conservative substitutions. In some embodiments, there maybe 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 conservativesubstitutions.

The term “amino acid substitution set” or “substitution set” refers to agroup of amino acid substitutions. A substitution set can have 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more amino acidsubstitutions.

The term “isolated” refers to a nucleic acid, polynucleotide,polypeptide, protein, or other component that is partially or completelyseparated from components with which it is normally associated (otherproteins, nucleic acids, cells, etc.). In some embodiments, an isolatedpolypeptide or protein is a recombinant polypeptide or protein.

A nucleic acid (such as a polynucleotide), a polypeptide, or a cell is“recombinant” when it is artificial or engineered, or derived from orcontains an artificial or engineered protein or nucleic acid (e.g.non-natural or not wild type). For example, a polynucleotide that isinserted into a vector or any other heterologous location, e.g., in agenome of a recombinant organism, such that it is not associated withnucleotide sequences that normally flank the polynucleotide as it isfound in nature is a recombinant polynucleotide. A protein expressed invitro or in vivo from a recombinant polynucleotide is an example of arecombinant polypeptide. Likewise, a polynucleotide sequence that doesnot appear in nature, for example a variant of a naturally occurringgene, is recombinant.

“Identity” or “percent identity,” in the context of two or morepolypeptide sequences, refers to two or more sequences or subsequencesthat are the same or have a specified percentage of amino acid residuesthat are the same (e.g., share at least about 70%, at least about 75%,at least about 80%, at least about 85%, at least about 88% identity, atleast about 89%, at least about 90%, at least about 91%, at least about92%, at least about 93%, at least about 94%, at least about 95%, atleast about 96%, at least about 97%, at least about 98%, or at leastabout 99% identity) over a specified region to a reference sequence,when compared and aligned for maximum correspondence over a comparisonwindow, or designated region as measured using a sequence comparisonalgorithms or by manual alignment and visual inspection.

Optimal alignment of sequences for comparison and determination ofsequence identity can be determined by a sequence comparison algorithmor by visual inspection (see, generally, Ausubel et al., infra). Whenoptimally aligning sequences and determining sequence identity by visualinspection, percent sequence identity is calculated as the number ofresidues of the test sequence that are identical to the referencesequence divided by the number of non-gap positions and multiplied by100. When using a sequence comparison algorithm, test and referencesequences are entered into a computer, subsequence coordinates andsequence algorithm program parameters are designated. The sequencecomparison algorithm then calculates the percent sequence identities forthe test sequences relative to the reference sequence, based on theprogram parameters as known in the art, for example BLAST or BLAST 2.0.For example, comparison can be conducted, e.g., by the local homologyalgorithm of Smith & Waterman, 1981, Adv. Appl. Math. 2:482, by thehomology alignment algorithm of Needleman & Wunsch, 1970, J. Mol. Biol.48:443, by the search for similarity method of Pearson & Lipman, 1988,Proc. Nat'l. Acad. Sci. USA 85:2444, or by computerized implementationsof these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the WisconsinGenetics Software Package, Genetics Computer Group, 575 Science Dr.,Madison, Wis.). Thus alignment can be carried out for sequences thathave deletions and/or additions, as well as those that havesubstitutions, as well as naturally occurring, e.g., polymorphic orallelic variants, and man-made variants.

The phrase “substantial sequence identity” or “substantial identity,” inthe context of two polypeptide sequences, refers to a sequence that hasat least 70% identity to a reference sequence. Percent identity can beany integer from 70% to 100%. Two polypeptide sequences that have 100%sequence identity are said to be “identical.” A polypeptide sequence issaid to have “substantial sequence identity” to a reference sequencewhen the sequences have at least about 70%, at least about 75%, at least80%, at least 85%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, or at least 99% or greater sequence identity as determined usingthe methods described herein, such as BLAST using standard parameters asdescribed above.

The term “expression” includes any step involved in the production ofthe polypeptide including, but not limited to, transcription,post-transcriptional modification, translation, post-translationalmodification, and secretion.

An amino acid or peptide is “heterologous” to another sequence withwhich it is operably linked if the two sequences are not associated innature.

A combinatorial chemical library is a collection of diverse chemicalcompounds generated by either chemical synthesis or biologicalsynthesis, by combining a number of chemical “building blocks” such asreagents. For example, a linear combinatorial chemical library such as apolypeptide library is formed by combining a set of chemical buildingblocks (amino acids) in every possible way for a given compound length(i.e., the number of amino acids in a polypeptide compound). Millions ofchemical compounds can be synthesized through such combinatorial mixingof chemical building blocks.

Preparation and screening of combinatorial chemical libraries is wellknown to those of skill in the art. Such combinatorial chemicallibraries include, but are not limited to, peptide libraries (see, e.g.,U.S. Pat. No. 5,010,175, Furka, Int. J. Pept. Prot. Res. 37:487-493(1991) and Houghton et al., Nature 354:84-88 (1991)). Other chemistriesfor generating chemical diversity libraries can also be used. Suchchemistries include, but are not limited to: peptoids (e.g., PCTPublication No. WO 91/19735), encoded peptides (e.g., PCT Publication WO93/20242), random bio-oligomers (e.g., PCT Publication No. WO 92/00091),benzodiazepines (e.g., U.S. Pat. No. 5,288,514), diversomers such ashydantoins, benzodiazepines and dipeptides (Hobbs et al., Proc. Nat.Acad. Sci. USA 90:6909-6913 (1993)), vinylogous polypeptides (Hagiharaet al., J. Amer. Chem. Soc. 114:6568 (1992)), nonpeptidalpeptidomimetics with glucose scaffolding (Hirschmann et al., J. Amer.Chem. Soc. 114:9217-9218 (1992)), analogous organic syntheses of smallcompound libraries (Chen et al., J. Amer. Chem. Soc. 116:2661 (1994)),oligocarbamates (Cho et al., Science 261:1303 (1993)), and/or peptidylphosphonates (Campbell et al., J. Org. Chem. 59:658 (1994)), nucleicacid libraries (see Ausubel, Berger and Sambrook, all supra), peptidenucleic acid libraries (see, e.g., U.S. Pat. No. 5,539,083), antibodylibraries (see, e.g., Vaughn et al., Nature Biotechnology, 14(3):309-314(1996) and PCT/US96/10287), carbohydrate libraries (see, e.g., Liang etal., Science, 274:1520-1522 (1996) and U.S. Pat. No. 5,593,853). Themethods above may be used to synthesize single molecular species forincorporation into a prodrug.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

The term “reactive oxygen species” or “ROS”, as used herein, is amolecule comprising a reactive oxygen having unpaired valence shellelectrons. Hydrogen peroxide, hydroxyl radical, superoxide anion, andhypochlorous acid are non-limiting examples of reactive oxygen species.

The term “ROS-reactive boronic ester”, as used herein, is a boronicester that is capable of being released from the remainder of thecompound upon contacting an ROS (e.g. hydrogen peroxide). The term“boronic ester” is used according to its plain ordinary meaning andrefers to a compound formed between a boronic acid and one or morealcohols.

The term “metal binding moiety”, as used herein, is a drug moiety thatforms an active, or more active, metal binding drug upon modification orremoval of the prodrug moiety. A metal binding drug is a drug that iscapable of coordinating one or more metal atoms.

The term “zinc binding moiety”, as used herein, is a metal bindingmoiety that forms an active, or more active, zinc binding drug uponmodification or removal of the prodrug moiety. A zinc binding drug is adrug that is capable of coordinating one or more zinc atoms. (e.g. azinc atom necessary for a protein's function).

The term “carbohydrate”, as used herein, is used herein according to itsplain ordinary meaning and refers to a molecule consisting of carbon,hydrogen and oxygen. “Saccharide” is used interchangeably with“carbohydrate”. Carbohydrates include monosaccharides, for exampleglucose, and ribose, and polysaccharides. A “carbohydrate moiety”, asused herein, is a monovalent carbohydrate. A carbohydrate or acarbohydrate moiety may be unsubstituted or it may be substituted withthe substituents described herein.

The term “glycosyl moiety”, as used herein, is a monovalentmonosaccharide.

The term “oxidatively-sensitive prodrug”, as used herein, is a prodrughaving a prodrug moiety that is modified or removed in the presence ofan oxidative compound. An “oxidative compound” is a chemical compoundthat has the ability to oxidize other substances (e.g. a reactive oxygenspecies such as hydrogen peroxide).

The term “metalloprotein”, as used herein, is a protein that iscoordinated to at least one metal atom.

The term “metalloenzyme”, as used herein, is a metalloprotein in whichthe coordinated metal atom participates in a reaction catalyzed by themetalloenzyme.

The term “metalloprotease” or “metalloproteinase”, as used herein, is aprotease enzyme that coordinates a metal atom in the protease activesite and the metal atom, often zinc or cobalt, participates in thereaction catalyzed by the enzyme. Participation by the metal atom may bedirect or may be mediated through another atom or molecule, for examplethe enzyme or a water molecule or another molecule.

The term “matrix metalloprotease” or “matrix metalloproteinase” or“MMP”, as used herein, is a metalloprotease of a family of proteasesgenerally capable of degrading extracellular matrix proteins. Certainmatrix metalloproteases are also capable of cleaving substrates that arenot extracellular matrix proteins.

Examples of matrix metalloproteases include, but are not limited toMMP1, MMP2, MMP3, MMP 7, MMP8, MMP 9, MMP10, MMP11, MMP12, MMP13, MMP14,MMP15, MMP16, MMP17, MMP18, MMP19, MMP20, MMP21, MMP23A, MMP23B, MMP24,MMP25, MMP26, MMP27, or MMP28.

The term “electron withdrawing group”, as used herein, is a moiety thatdraws electrons or electron density to itself from an adjacent chemicalmoiety or atom.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

II. Compounds

In a first aspect, a compound is provided having the formula:

Within formula (I), (Ia), (II), (III), (IIIa) and (IV), A, B, C, and Dare independently a drug moiety. L¹ is a bond or unsubstituted alkylene.X¹ is —NH— or —O—. R¹ is independently —B(OH)₂, an ROS-reactive boronicester, hydrogen, halogen, —CN, —SR^(13B), —SO₂Cl, —SO₃H, —SO₄H,—SO₂NR^(7B)R^(8B), —NHNH₂, —ONR^(7B)R^(8B), —NHC═(O)NHNH₂,—NHC═(O)NR^(7B)R^(8B), —N(O)_(m), —NR^(7B)R^(8B), —C(O)R^(9B),—C(O)—OR^(10B), —C(O)NR^(11B)R^(12B), —OR^(13B), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, peptidyl, or peptidomimetic moiety. In someembodiments, R¹ is —B(OH)₂ or an ROS-reactive boronic ester. In someembodiments, R¹ is —B(OH)₂. In some embodiments, R¹ is an ROS-reactiveboronic ester. In some embodiments, R¹ is boronic acid pinacol ester. Insome embodiments, L¹ is a bond. In some embodiments, L¹ is anunsubstituted alkylene (e.g. an unsubstituted C₁-C₅ alkylene such asmethylene). In some embodiments, X¹ is —NH—. In some embodiments, X¹ is—O—. In other embodiments, X¹ is —NH— and L¹ is an unsubstitutedalkylene (e.g. an unsubstituted C₁-C₅ alkylene such as methylene). WhereX¹ is —O—, L¹ may be a bond.

R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), and R^(13B) areindependently hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, peptidyl or peptidomimeticmoiety.

R² is independently hydrogen, halogen, —CN, —SR^(13B), —SO₂Cl, —SO₃H,—SO₄H, —SO₂NR^(7B)R^(8B), —NHNH₂, —ONR^(7B)R^(8B), —NHC═(O)NHNH₂,—NHC═(O)NR^(7B)R^(8B), —N(O)_(m), —NR^(7B), R^(8B), —C(O)R^(9B),—C(O)—OR^(10B), C(O)—NR^(11B)R^(12B), —OR^(13B), substituted orunsubstituted alkyl (e.g. methyl), substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, an electron withdrawing group,peptidyl, or peptidomimetic moiety. In some embodiments, R² isindependently halogen, —CN, —N(O)₂, —COOH, substituted or unsubstitutedalkyl (e.g. a substituted or unsubstituted C₁-C₅ alkyl such as methyl),substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,peptidyl, peptidomimetic moiety, or an electron withdrawing group. Thesymbol z is an integer from 0 to 5. The symbol m is an integer from 1 to2. In some embodiments, z is 1. In another embodiment, z is 2. In afurther embodiment, z is 3. In yet another embodiment, z is 4. In afurther embodiment, z is 5. In another embodiment, z is 0. In someembodiments, m is 1. In some embodiments, m is 2.

In an embodiment, z is 2 and R¹ and R² are at the ortho and parapositions relative to the drug moiety (e.g. drug moiety bonded to thesulfonyl group in the case of R²).

In one embodiment z is 1 and R² is para-N(O)₂. In another embodiment, zis 1 and R² is para-methyl. In a further embodiment, z is 2 and R² isortho-N(O)₂ and para-N(O)₂. In one embodiment, z is 1 and R² ispara-COOH.

In one embodiment R² is unsubstituted alkyl. In one embodiment R² isunsubstituted C₁-C₈ alkyl. In one embodiment R² is unsubstituted C₁-C₃alkyl. In one embodiment R² is methyl. In another embodiment, R² is—N(O)₂, methyl or —COOH.

In some embodiments, the compound is an oxidatively-sensitive prodrugthat forms a drug upon exposure to an oxidative compound. In someembodiments, the drug moiety is a metal binding moiety. In someembodiments, the metal binding moiety is a zinc binding moiety.

In some embodiments, the drug moiety is capable of forming a drug (incombination with a chemical moiety resulting from the prodrug moietyreaction) following modification or separation of the drug moiety fromthe oxidatively-sensitive prodrug moiety. In some embodiments, the drugformed from the drug moiety is selected from retinoic acid, retinol,tretinoin, isotretinoin. In some embodiments, the drug is a matrixmetalloprotease inhibitor. In some embodiments, the drug is doxycycline,minocycline, a tetracycline, marimastat, BB-2516, cipemastat,Ro-32-3555. In some embodiments, the drug comprises a hydroxamate. Insome embodiments, the drug includes a phosphinyl. In some embodiments,the drug is selected from 1,2-hydroxypyridinone,3-hydroxy-2-methyl-4H-pyran-4-one,3-hydroxy-1,2-dimethylpyridin-4(1H)-one, tropolone, methyl salicylate,or 8-hydroxyquinoline.

In some embodiments, A and C are independently

R³ is halogen, —CN, —SR¹³, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NR⁷R⁸, —NHNH₂,—ONR⁷R⁸, —NHC═(O)NHNH₂, —NHC═(O)NR⁷R⁸, N(O)_(m), —NR⁷R⁸, —C(O)R⁹,—C(O)—OR¹⁰, —C(O)NR¹¹R¹², —OR¹³, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, apeptidyl, or peptidomimetic moiety. In some embodiments, R³ is hydrogen,halogen, —CN, —SR¹³, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NR⁷R⁸, —NHNH₂, —ONR⁷R⁸,—NHC═(O)NHNH₂, —NHC═(O)NR⁷R⁸, —N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR¹⁰,—C(O)NR¹¹R¹², —OR¹³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl. In oneembodiment, R³ is a substituted or unsubstituted alkylamido.

The symbol m is 1 or 2. In some embodiments, m is 1. In anotherembodiment, m is 2.

R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are independently hydrogen, halogen,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂₅—NHC═(O)NHNH₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,peptidyl, or peptidomimetic moiety.

In some embodiments, R³ is a peptidyl, peptidyl-substituted alkyl,peptidyl-substituted heteroalkyl, peptidyl-substituted cycloalkyl,peptidyl-substituted heterocycloalkyl, peptidyl-substituted aryl, orpeptidyl-substituted heteroaryl. In some embodiments, R³ is apeptidomimetic moiety, peptidomimetic substituted alkyl, peptidomimeticsubstituted heteroalkyl, peptidomimetic substituted cycloalkyl,peptidomimetic substituted heterocycloalkyl, peptidomimetic substitutedaryl, or peptidomimetic substituted heteroaryl.

R⁴ is hydrogen, halogen, —CN, —OH, —NH₂, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —C(O)R^(9A),—C(O)—OR^(10A), —C(O)NR^(11A)R^(12A), —OR^(13A), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substitutedunsubstituted heteroaryl, peptidyl, or peptidomimetic moiety.

R^(9A), R^(10A), R^(11A), R^(12A), and R^(13A) are independentlyhydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, peptidyl or peptidomimetic moiety.

In some embodiments, R⁴ is hydrogen, halogen, —C(O)R^(9A),—C(O)—OR^(10A), —C(O)NR^(11A), R^(12A), —OR^(13A), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. In some embodiments, R^(9A), R^(10A), R^(11A),R^(12A), and R^(13A) are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In some embodiments, R⁴ is hydrogen, orsubstituted or unsubstituted alkyl.

R⁵ is hydrogen, halogen, —CN, —OH, —NH₂, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —C(O)R^(9A),—C(O)—OR^(10A), —C(O)NR^(11A), R^(12A), —OR^(13A), substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, peptidyl or peptidomimetic moiety. In someembodiments, R⁵ is hydrogen, halogen, —C(O)R^(9A), —C(O)—OR^(10A),—C(O)NR^(11A)R^(12A), —OR^(13A), substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl. In someembodiments, R⁵ is hydrogen or substituted or unsubstituted alkyl. Insome embodiments, R⁵ is unsubstituted alkyl. In one embodiment, R⁵ isunsubstituted C₁-C₈ alkyl. In one embodiment R⁵ is unsubstituted C₁-C₃alkyl. In one embodiment R⁵ is methyl.

The symbols a, e, and f are independently an integer from 0 to 4 (e.g. 1to 4). In further separate embodiments, a is 1. In further separateembodiments, a is 2. In further separate embodiments, a is 3. In furtherseparate embodiments, a is 4. In further separate embodiments, e is 1.In further separate embodiments, e is 2. In further separateembodiments, e is 3. In further separate embodiments, e is 4. In furtherseparate embodiments, f is 1. In further separate embodiments, f is 2.In further separate embodiments, f is 3. In further separateembodiments, f is 4. In some embodiments, a is 0. In some embodiments, eis 0. In some embodiments, f is 0.

The symbols b and d are independently an integer from 0 to 3 (e.g. 1 to3). In further separate embodiments, b is 1. In further separateembodiments, b is 2. In further separate embodiments, b is 3. In furtherseparate embodiments, d is 1. In further separate embodiments, d is 2.In further separate embodiments, d is 3. The symbol c is an integer from1 to 5. In further separate embodiments, c is 1. In further separateembodiments, c is 2. In further separate embodiments, c is 3. In furtherseparate embodiments, c is 4. In further separate embodiments, c is 5.In some embodiments, b is 0. In some embodiments, d is 0. In someembodiments, c is 0.

The symbol g is an integer from 0 to 6 (e.g. 1 to 6). In furtherseparate embodiments, g is 1. In further separate embodiments, g is 2.In further separate embodiments, g is 3. In further separateembodiments, g is 4. In further separate embodiments, g is 5. In furtherseparate embodiments, g is 6. In some embodiments, g is 0.

X is ═O or ═S. In some embodiments X is ═O. In some embodiments X is ═S.In some embodiments, L¹ is a bond. In some embodiments, L¹ isunsubstituted alkylene. In some embodiments, L¹ is methylene. In someembodiments, X¹ is —NH—. In some embodiments, X¹ is —O—.

In some embodiments B is:

R³ and X are as defined above, including embodiments. The symbol h is aninteger from 0 to 4 (e.g. 1 to 4). In further separate embodiments, his 1. In further separate embodiments, h is 2. In further separateembodiments, h is 3. In further separate embodiments, h is 4. In someembodiments, h is 0.

In one embodiment, C is

R³, R⁴, R⁵, X, a, b, c, d, e, f and g are as defined above, includingembodiments.

In some embodiments, D is

R³, R⁴, R⁵, X, a, b, c, d, e, f and g are as defined above, includingembodiments.

In any of the above embodiments, R³ may be a peptidyl, peptidomimeticmoiety or other suitable moiety for interacting with the protein,metalloprotein, metalloenzyme, or metalloprotease of interest. Suitablebackbones for such interactions are known in the art, for example see,Rao G., Curr Pharm Des. 2005; 11(3):295-322; Whittaker, et. al. Chem.Rev. 1999, 99, 2735-2776; European Patent Application No. 126,974;International Application Publication No. WO 2006/028523 and U.S.Application Publication No. 2005/0267102.

In any of the above embodiments, R³ may be any of the organic radicalsderived from the structures shown on Scheme 1 of the Whittaker, et. al.Chem. Rev. 1999, 99, 2735-2776, after removal of the C(O)NH(OH) group.In some embodiments, R³ includes a naturally-occurring peptide, asynthetic peptide or a peptide analog (peptidomimetic). Such groups maycontain one or more amido moieties (—C(O)NH—), which can be or contain,peptidyl bonds. In some embodiments, R³ includes a peptide of 1 to 20amino acids of amino acid mimetics

In any of the above embodiments, R³ may be biphenylcarbamyl,biphenylcarbamylalkyl, biphenylalkylcarbamyl,biphenylalkylcarbamylalkyl, phenoxyphenylcarbamyl, arylalkylaminoalkyl,biphenylalkylaminoalkyl, arylcarbonylaminoalkyl,arylalkylcarbonylaminoalkyl, biphenyloxyalkylcarbonylaminoalkyl, orphenoxyphenylcarbamylalkyl, wherein, the phenyl or aryl group(s) may beoptionally substituted, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, R³ may be

In any of the above embodiments, R³ may be unsubstituted or substitutedwith one or more substituents, in one embodiment one to fivesubstituents, in another embodiment one, two or three substituents, eachindependently selected from Q¹; where Q¹ is hydrogen, halo, pseudohalo,hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,alkyl, haloalkyl, aminoalkyl, diaminoalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, aralkyl, aralkenyl, aralkynyl, alkylcarbonyl, aminocarbonyl,alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkoxy,alkenyloxy, alkynyloxy, aralkoxy, amino, aminoalkyl, alkylamino,arylamino, alkylthio, arylthio, thiocyano, isothiocyano, and each Q¹ isindependently unsubstituted or substituted with one or moresubstituents, in one embodiment one, two or three substituents, eachindependently selected from Q²; each Q² is independently hydrogen, halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, alkyl, haloalkyl, aminoalkyl, diaminoalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, alkylcarbonyl,aminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy,cycloalkoxy, alkenyloxy, alkynyloxy, aralkoxy, amino, aminoalkyl,alkylamino, arylamino, alkylthio, arylthio, thiocyano or isothiocyano.

In another aspect, is a compound having the formula

E is a drug moiety. L² is independently a bond, —O—, —S—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. R⁶ is asubstituted or unsubstituted carbohydrate moiety. In one embodiment, Eis a metal binding moiety. In a further embodiment, E is a zinc bindingmoiety. Where R⁶ is typically attached to the remainder of the compoundvia a glycosidic bond (e.g. an ether). In some embodiments, where L² is—O—, L² serves as the glycosidic bond.

In a further embodiment, R⁶ is a substituted or unsubstituted glycosylmoiety. In another embodiment, R⁶ is substituted or unsubstitutedhexosyl moiety. In another embodiment, R⁶ is a substituted orunsubstituted pentosyl moiety. In another embodiment, R⁶ is asubstituted or unsubstituted heptosyl moiety. In another embodiment, R⁶is a substituted or unsubstituted monosaccharide moiety. In anotherembodiment, R⁶ is a substituted or unsubstituted disaccharide moiety. Inanother embodiment, R⁶ is a substituted or unsubstituted polysaccharidemoiety. In a further embodiment, R⁶ is a substituted or unsubstitutedglucosyl moiety.

In one embodiment, E is

R³, R⁴, R⁵, X, a, b, c, d, e, f and g are as defined above, includingembodiments.

In some embodiments, the compound is an oxidatively-sensitive prodrug.The oxidatively-sensitive prodrug may be a compound set forth herein(e.g. a compound of formula I, Ia, II, III, IIIa, or IV).

In some embodiments, the compound is an oxidatively-sensitive prodrugthat forms a drug upon exposure to an oxidative compound. In oneembodiment, A, B, C, D, and E are independently a metal binding moiety.In a further embodiment, the metal binding moiety is a zinc bindingmoiety. In some embodiments, the compound is an oxidatively-sensitiveprodrug that forms a metal binding compound upon exposure to anoxidative compound. In some embodiments, the compound of formula I mayform a drug having the formula A-OH. In some embodiments, the compoundof formula II may form a drug having the formula B—OH. In someembodiments, the compound of formula III may form a drug having theformula C-L¹-X¹—H. In some embodiments, the compound of formula IIIa mayform a drug having the formula C-L¹-X¹—H. L¹ and X¹ are as definedherein, including embodiments. In some embodiments, the compound offormula IV may form a drug having the formula D-OH. In some embodiments,the compound of formula V may form a drug having the formula E-L²-H. L²is as defined herein, including embodiments.

In another embodiment, the metal binding moiety is attached (e.g.covalently bonded) to a hydroxyl group following reaction of thecompound with an ROS. The hydroxylated metal binding moiety that isformed is a metal binding compound or drug. In a further embodiment, themetal binding moiety of formula (III) or (Ma) in which X¹ is —NH—, isattached to an amine group following reaction of the compound with anROS and the aminated metal binding moiety is a metal binding compound.In another embodiment, the drug moiety is attached to a hydroxyl groupfollowing reaction of the compound with an ROS and the hydroxylated drugmoiety is a drug that is known to be useful in the treatment of adisease. In a further embodiment, the drug moiety of formula (III) or(IIIa) in which X¹ is —NH—, is attached to an amine group followingreaction of the compound with an ROS and the aminated drug moiety is adrug known to be useful for the treatment of a disease.

In another embodiment, the ROS-reactive boronic ester is capable ofreacting with hydrogen peroxide. Upon reacting, a drug is formed fromthe compound of formula I, IA, II, III, IIIa, or IV. In anotherembodiment, the ROS-reactive boronic ester is a boronic acid pinacolester. In a further embodiment, the ROS-reactive boronic ester has theformula —B(OR⁵³)(OR⁵⁷). R⁵³ and R⁵⁷ are independently halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, peptidyl,or peptidomimetic moiety. In a further embodiment, the ROS-reactiveboronic ester has the formula —B(OR⁵³)(OR⁵⁷) wherein R⁵³ and R⁵⁷ areindependently substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R⁵³ and R⁵⁷ form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Insome embodiments, R⁵³ and R⁵⁷ form a substituted or unsubstituted fusedring heterocycloalkyl-aryl, substituted or unsubstituted fused ringheterocycloalkyl-heteroaryl, substituted or unsubstituted fused ringheterocycloalkyl-cycloalkyl, or a substituted or unsubstituted fusedring heterocycloalkyl-heterocycloalkyl. In some embodiments, R⁵³ and R⁵⁷form a substituted or unsubstituted heterocycloalkyl or a substituted orunsubstituted heteroaryl ring. In some embodiments, R⁵³ and R⁵⁷ form afive membered substituted or unsubstituted heterocycloalkyl or a fivemembered substituted or unsubstituted heteroaryl ring.

In some embodiments, an ROS-reactive boronic ester comprises thecompound of formula (VIII):

In some embodiments, a boronic ester is a compound of formula (VIII).R⁷², R⁷³, R⁷⁴, and R⁷⁵, are independently hydrogen, halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, peptidyl,or peptidomimetic moiety. In some embodiments, two of R⁷², R⁷³, R⁷⁴, andR⁷⁵ form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl ring. In some embodiments, thesubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl ring is a fused ring. In some embodiments, R⁷²and R⁷³ or R⁷⁴ and R⁷⁵ or both pairs of substituents independently forma substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl ring. In some embodiments, R⁷² and R⁷³ or R⁷⁴and R⁷⁵ both independently form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl ringand the R⁷² and R⁷³ or R⁷⁴ and R⁷⁵ rings are not identical. In someembodiments, R⁷² and R⁷³ form a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl ring andthe R⁷² and R⁷³ or R⁷⁴ and R⁷⁵ rings are not identical. In anotherembodiment, the R⁷² and R⁷³ or R⁷⁴ and R⁷⁵ rings are identical. In someembodiments, a boronic ester is a boronic acid pinacol ester and R⁷²,R⁷³, R⁷⁴, and R⁷⁵ are methyl.

In separate embodiments of any aspect herein, R⁵³, R⁵⁷, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently substituted or unsubstituted C₁-C₅ alkyl, substitutedor unsubstituted 2 to 5 membered heteroalkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, or substituted, unsubstituted 5 or 6membered heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In some embodiments, a compound of formula (I), (Ia), (II), (III),(IIIa), (IV), or (V) includes one or more peptidyl moieties. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently apeptidyl-substituted alkyl, peptidyl-substituted heteroalkyl,peptidyl-substituted cycloalkyl, peptidyl-substituted heterocycloalkyl,peptidyl-substituted aryl, or peptidyl-substituted heteroaryl. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11A), R^(12B), or R^(13B) are independently a peptidyl. Insome embodiments, only one of R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B),R^(8B), R^(9B), R^(11B), R^(11B), R^(12B), or R^(13B) is or includes apeptidyl or peptidomimetic moiety.

In some embodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B),R^(9B), R^(11B), R^(11B), R^(12B), or R^(13B) are independently apeptidyl having two amino acids. In some embodiments R⁵³, R⁵⁷, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A),R^(12A), R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), orR^(13B) are independently a peptidyl having 3 amino acids. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently a peptidylhaving 4 amino acids. In some embodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently a peptidyl having 5 amino acids. In some embodiments,R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A),R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B), R^(10B),R^(11B), R^(12B), or R^(13B) are independently a peptidyl having 6 aminoacids. In some embodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B),R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B) are independentlya peptidyl having 7 amino acids. In some embodiments R⁵³, R⁵⁷, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A),R^(12A), R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), orR^(13B) are independently a peptidyl having 8 amino acids. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently a peptidylhaving 9 amino acids. In some embodiments R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently a peptidyl having 10 amino acids. In some embodiments,R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A),R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B), R^(10B),R^(11B), R^(12B), or R^(13B) are independently a peptidyl having 15amino acids. In some embodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A),R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B) areindependently a peptidyl having 20 amino acids. In some embodiments,R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A),R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B), R^(10B),R^(11B), R^(12B), or R^(13B) are independently a peptidyl substantiallyidentical to the amino acid sequence of a substrate of ametalloprotease.

In some embodiments, a compound of formula (I), (Ia), (II), (III),(IIIa), (IV), or (V) includes one or more peptidomimetic moieties. Insome embodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B),R^(9B), R^(11B), R^(11B), R^(12B), or R^(13B) are independently apeptidomimetic substituted alkyl, peptidomimetic substitutedheteroalkyl, peptidomimetic substituted cycloalkyl, peptidomimeticsubstituted heterocycloalkyl, peptidomimetic substituted aryl, orpeptidomimetic substituted heteroaryl. In some embodiments, R⁵³, R⁵⁷,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A),R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B),R^(12B), or R^(13B) are independently a peptidomimetic moiety. In someembodiments R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently a two amino acidpeptidomimetic moiety. In some embodiments, R⁵³, R⁵⁷, R², R³, R⁴R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently a 3 amino acid peptidomimetic moiety. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(11B), R^(11B), R^(12B), or R^(13B) are independently a 4 amino acidpeptidomimetic moiety. In some embodiments, R R⁵³, R⁵⁷, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently a 5 amino acid peptidomimetic moiety. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently a 6 amino acidpeptidomimetic moiety. In some embodiments R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently a 7 amino acid peptidomimetic moiety. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵R⁶R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently a 8 amino acidpeptidomimetic moiety. In some embodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently a 9 amino acid peptidomimetic moiety. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently a 10 amino acidpeptidomimetic moiety. In some embodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12B), or R^(13B)are independently a 15 amino acid peptidomimetic moiety. In someembodiments, R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R^(9A), R^(10A), R^(11A), R^(12A), R^(13A), R^(7B), R^(8B), R^(9B),R^(10B), R^(11B), R^(12B), or R^(13B) are independently a 20 amino acidpeptidomimetic moiety. In some embodiments R⁵³, R⁵⁷, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R^(9A), R^(10A), R^(11A), R^(12A),R^(13A), R^(7B), R^(8B), R^(9B), R^(10B), R^(11B), R^(12A), or R^(13B)are independently a peptidomimetic moiety substantially identical to theamino acid sequence of a substrate of a metalloprotease.

In some embodiments, R¹ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂₅—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R¹⁴—substituted or unsubstituted alkyl, R¹⁴-substitutedor unsubstituted heteroalkyl, R¹⁴-substituted or unsubstitutedcycloalkyl, R¹⁴-substituted or unsubstituted heterocycloalkyl,R¹⁴-substituted or unsubstituted aryl, or R¹⁴-substituted orunsubstituted heteroaryl.

R¹⁴ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R¹⁵-substituted or unsubstituted alkyl, R¹⁵-substituted or unsubstitutedheteroalkyl, R¹⁵-substituted or unsubstituted cycloalkyl,R¹⁵-substituted or unsubstituted heterocycloalkyl, R¹⁵-substituted orunsubstituted aryl, or R¹⁵-substituted or unsubstituted heteroaryl.

R¹⁵ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R¹⁶-substituted or unsubstituted alkyl, R¹⁶-substituted or unsubstitutedheteroalkyl, R¹⁶-substituted or unsubstituted cycloalkyl,R¹⁶-substituted or unsubstituted heterocycloalkyl, R¹⁶-substituted orunsubstituted aryl, or R¹⁶-substituted or unsubstituted heteroaryl.

In some embodiments, R² is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂₅—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R¹⁷-substituted or unsubstituted alkyl, R¹⁷-substitutedor unsubstituted heteroalkyl, R¹⁷-substituted or unsubstitutedcycloalkyl, R¹⁷-substituted or unsubstituted heterocycloalkyl,R¹⁷-substituted or unsubstituted aryl, or R¹⁷-substituted orunsubstituted heteroaryl.

R¹⁷ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R¹⁸-substituted or unsubstituted alkyl, R¹⁸-substituted or unsubstitutedheteroalkyl, R¹⁸-substituted or unsubstituted cycloalkyl,R¹⁸-substituted or unsubstituted heterocycloalkyl, R¹⁸-substituted orunsubstituted aryl, or R¹⁸-substituted or unsubstituted heteroaryl.

R¹⁸ independently is halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R¹⁹-substituted or unsubstituted alkyl, R¹⁹-substituted or unsubstitutedheteroalkyl, R¹⁹-substituted or unsubstituted cycloalkyl,R¹⁸-substituted or unsubstituted heterocycloalkyl, R¹⁸-substituted orunsubstituted aryl, or R¹⁸-substituted or unsubstituted heteroaryl.

In some embodiments, R³ is halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R²⁰-substituted or unsubstituted alkyl, R²⁰-substituted or unsubstitutedheteroalkyl, R²⁰-substituted or unsubstituted cycloalkyl,R²⁰-substituted or unsubstituted heterocycloalkyl, R²⁰-substituted orunsubstituted aryl, or R²⁰-substituted or unsubstituted heteroaryl.

R²⁰ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R²¹-substituted or unsubstituted alkyl, R²¹-substituted or unsubstitutedheteroalkyl, R²¹-substituted or unsubstituted cycloalkyl, R²¹substituted or unsubstituted heterocycloalkyl, R²¹-substituted orunsubstituted aryl, or R²¹-substituted or unsubstituted heteroaryl.

R²¹ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R²²-substituted or unsubstituted alkyl, R²²-substituted or unsubstitutedheteroalkyl, R²²-substituted or unsubstituted cycloalkyl,R²²-substituted or unsubstituted heterocycloalkyl, R²²-substituted orunsubstituted aryl, or R²²-substituted or unsubstituted heteroaryl.

In some embodiments, R⁴ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R²³-substituted or unsubstituted alkyl, R²³-substitutedor unsubstituted heteroalkyl, R²³-substituted or unsubstitutedcycloalkyl, R²³-substituted or unsubstituted heterocycloalkyl,R²³-substituted or unsubstituted aryl, or R²³-substituted orunsubstituted heteroaryl.

R²³ independently is halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R²⁴-substituted or unsubstituted alkyl, R²⁴-substituted or unsubstitutedheteroalkyl, R²⁴-substituted or unsubstituted cycloalkyl, R²⁴substituted or unsubstituted heterocycloalkyl, R²⁴-substituted orunsubstituted aryl, or R²⁴-substituted or unsubstituted heteroaryl.

R²⁴ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R²⁵-substituted or unsubstituted alkyl, R²⁵-substituted or unsubstitutedheteroalkyl, R²⁵-substituted or unsubstituted cycloalkyl,R²⁵-substituted or unsubstituted heterocycloalkyl, R²⁵-substituted orunsubstituted aryl, or R²⁵-substituted or unsubstituted heteroaryl.

In some embodiments, R⁵ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R²⁶-substituted or unsubstituted alkyl, R²⁶-substitutedor unsubstituted heteroalkyl, R²⁶-substituted or unsubstitutedcycloalkyl, R²⁶-substituted or unsubstituted heterocycloalkyl,R²⁶-substituted or unsubstituted aryl, or R²⁶-substituted orunsubstituted heteroaryl.

R²⁶ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R²⁷-substituted or unsubstituted alkyl, R²⁷-substituted or unsubstitutedheteroalkyl, R²⁷-substituted or unsubstituted cycloalkyl, R²⁷substituted or unsubstituted heterocycloalkyl, R²⁷-substituted orunsubstituted aryl, or R²⁷-substituted or unsubstituted heteroaryl.

R²⁷ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R²⁸-substituted or unsubstituted alkyl, R²⁸-substituted or unsubstitutedheteroalkyl, R²⁸-substituted or unsubstituted cycloalkyl,R²⁸-substituted or unsubstituted heterocycloalkyl, R²⁸-substituted orunsubstituted aryl, or R²⁸-substituted or unsubstituted heteroaryl.

In some embodiments, R⁶ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R²⁹— substituted or unsubstituted alkyl, R²⁹-substitutedor unsubstituted heteroalkyl, R²⁹-substituted or unsubstitutedcycloalkyl, R²⁹-substituted or unsubstituted heterocycloalkyl,R²⁹-substituted or unsubstituted aryl, or R²⁹-substituted orunsubstituted heteroaryl.

R²⁹ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R³⁰-substituted or unsubstituted alkyl, R³⁰-substituted or unsubstitutedheteroalkyl, R³⁰-substituted or unsubstituted cycloalkyl, R³⁰substituted or unsubstituted heterocycloalkyl, R³⁰-substituted orunsubstituted aryl, or R³⁰-substituted or unsubstituted heteroaryl.

R³⁰ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R³¹-substituted or unsubstituted alkyl, R³¹-substituted or unsubstitutedheteroalkyl, R³¹-substituted or unsubstituted cycloalkyl,R³¹-substituted or unsubstituted heterocycloalkyl, R³¹-substituted orunsubstituted aryl, or R³¹-substituted or unsubstituted heteroaryl.

In some embodiments, R⁷ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R³²-substituted or unsubstituted alkyl, R³²-substitutedor unsubstituted heteroalkyl, R³²-substituted or unsubstitutedcycloalkyl, R³²-substituted or unsubstituted heterocycloalkyl,R³²-substituted or unsubstituted aryl, or R³²-substituted orunsubstituted heteroaryl.

R³² is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R³³-substituted or unsubstituted alkyl, R³³-substituted or unsubstitutedheteroalkyl, R³³-substituted or unsubstituted cycloalkyl, R³³substituted or unsubstituted heterocycloalkyl, R³³-substituted orunsubstituted aryl, or R³³-substituted or unsubstituted heteroaryl.

R³³ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R³⁴-substituted or unsubstituted alkyl, R³⁴-substituted or unsubstitutedheteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl,R³⁴-substituted or unsubstituted heterocycloalkyl, R³⁴-substituted orunsubstituted aryl, or R³⁴-substituted or unsubstituted heteroaryl.

In some embodiments, R⁸ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R³⁵-substituted or unsubstituted alkyl, R³⁵-substitutedor unsubstituted heteroalkyl, R³⁵-substituted or unsubstitutedcycloalkyl, R³⁵-substituted or unsubstituted heterocycloalkyl,R³⁵-substituted or unsubstituted aryl, or R³⁵-substituted orunsubstituted heteroaryl.

R³⁵ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R³⁶-substituted or unsubstituted alkyl, R³⁶-substituted or unsubstitutedheteroalkyl, R³⁶-substituted or unsubstituted cycloalkyl, R³⁶substituted or unsubstituted heterocycloalkyl, R³⁶-substituted orunsubstituted aryl, or R³⁶-substituted or unsubstituted heteroaryl.

R³⁶ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R³⁷-substituted or unsubstituted alkyl, R³⁷-substituted or unsubstitutedheteroalkyl, R³⁷-substituted or unsubstituted cycloalkyl,R³⁷-substituted or unsubstituted heterocycloalkyl, R³⁷-substituted orunsubstituted aryl, or R³⁷-substituted or unsubstituted heteroaryl.

In some embodiments, R⁹ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R³⁸-substituted or unsubstituted alkyl, R³⁸-substitutedor unsubstituted heteroalkyl, R³⁸-substituted or unsubstitutedcycloalkyl, R³⁸-substituted or unsubstituted heterocycloalkyl,R³⁸-substituted or unsubstituted aryl, or R³⁸-substituted orunsubstituted heteroaryl.

R³⁸ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R³⁹-substituted or unsubstituted alkyl, R³⁹-substituted or unsubstitutedheteroalkyl, R³⁹-substituted or unsubstituted cycloalkyl, R³⁹substituted or unsubstituted heterocycloalkyl, R³⁹-substituted orunsubstituted aryl, or R³⁹-substituted or unsubstituted heteroaryl.

R³⁹ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴⁰-substituted or unsubstituted alkyl, R⁴⁰-substituted or unsubstitutedheteroalkyl, R⁴⁰-substituted or unsubstituted cycloalkyl,R⁴⁰-substituted or unsubstituted heterocycloalkyl, R⁴⁰-substituted orunsubstituted aryl, or R⁴⁰-substituted or unsubstituted heteroaryl.

In some embodiments, R¹⁰ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R⁴¹-substituted or unsubstituted alkyl, R⁴¹-substitutedor unsubstituted heteroalkyl, R⁴¹-substituted or unsubstitutedcycloalkyl, R⁴¹-substituted or unsubstituted heterocycloalkyl,R⁴¹-substituted or unsubstituted aryl, or R⁴¹-substituted orunsubstituted heteroaryl.

R⁴¹ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴²-substituted or unsubstituted alkyl, R⁴²-substituted or unsubstitutedheteroalkyl, R⁴²-substituted or unsubstituted cycloalkyl, R⁴²substituted or unsubstituted heterocycloalkyl, R⁴²-substituted orunsubstituted aryl, or R⁴²-substituted or unsubstituted heteroaryl.

R⁴² is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴³-substituted or unsubstituted alkyl, R⁴³-substituted or unsubstitutedheteroalkyl, R⁴³-substituted or unsubstituted cycloalkyl,R⁴³-substituted or unsubstituted heterocycloalkyl, R⁴³-substituted orunsubstituted aryl, or R⁴³-substituted or unsubstituted heteroaryl.

In some embodiments, R¹¹ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R⁴⁴-substituted or unsubstituted alkyl, R⁴⁴-substitutedor unsubstituted heteroalkyl, R⁴⁴-substituted or unsubstitutedcycloalkyl, R⁴⁴-substituted or unsubstituted heterocycloalkyl,R⁴⁴-substituted or unsubstituted aryl, or R⁴⁴-substituted orunsubstituted heteroaryl.

R⁴⁴ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴⁵-substituted or unsubstituted alkyl, R⁴⁵-substituted or unsubstitutedheteroalkyl, R⁴⁵-substituted or unsubstituted cycloalkyl, R⁴⁵substituted or unsubstituted heterocycloalkyl, R⁴⁵-substituted orunsubstituted aryl, or R⁴⁵-substituted or unsubstituted heteroaryl.

R⁴⁵ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴⁶-substituted or unsubstituted alkyl, R⁴⁶-substituted or unsubstitutedheteroalkyl, R⁴⁶-substituted or unsubstituted cycloalkyl,R⁴⁶-substituted or unsubstituted heterocycloalkyl, R⁴⁶-substituted orunsubstituted aryl, or R⁴⁶-substituted or unsubstituted heteroaryl.

In some embodiments, R¹² is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R⁴⁷-substituted or unsubstituted alkyl, R⁴⁷-substitutedor unsubstituted heteroalkyl, R⁴⁷-substituted or unsubstitutedcycloalkyl, R⁴⁷-substituted or unsubstituted heterocycloalkyl,R⁴⁷-substituted or unsubstituted aryl, or R⁴⁷-substituted orunsubstituted heteroaryl.

R⁴⁷ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴⁸-substituted or unsubstituted alkyl, R⁴⁸-substituted or unsubstitutedheteroalkyl, R⁴⁸-substituted or unsubstituted cycloalkyl, R⁴⁸substituted or unsubstituted heterocycloalkyl, R⁴⁸-substituted orunsubstituted aryl, or R⁴⁸-substituted or unsubstituted heteroaryl.

R⁴⁸ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴⁹-substituted or unsubstituted alkyl, R⁴⁹-substituted or unsubstitutedheteroalkyl, R⁴⁹-substituted or unsubstituted cycloalkyl,R⁴⁹-substituted or unsubstituted heterocycloalkyl, R⁴⁹-substituted orunsubstituted aryl, or R⁴⁹-substituted or unsubstituted heteroaryl.

In some embodiments, R¹³ is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R⁵⁰-substituted or unsubstituted alkyl, R⁵⁰-substitutedor unsubstituted heteroalkyl, R⁵⁰-substituted or unsubstitutedcycloalkyl, R⁵⁰-substituted or unsubstituted heterocycloalkyl,R⁵⁰-substituted or unsubstituted aryl, or R⁵⁰-substituted orunsubstituted heteroaryl.

R⁵⁰ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁵¹-substituted or unsubstituted alkyl, R⁵¹-substituted or unsubstitutedheteroalkyl, R⁵¹-substituted or unsubstituted cycloalkyl, R⁵¹substituted or unsubstituted heterocycloalkyl, R⁵¹-substituted orunsubstituted aryl, or R⁵¹-substituted or unsubstituted heteroaryl.

R⁵¹ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁵²-substituted or unsubstituted alkyl, R⁵²-substituted or unsubstitutedheteroalkyl, R⁵²-substituted or unsubstituted cycloalkyl,R⁵²-substituted or unsubstituted heterocycloalkyl, R⁵²-substituted orunsubstituted aryl, or R⁵²-substituted or unsubstituted heteroaryl.

In a further embodiment, R⁵³ is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R⁵⁴-substituted or unsubstituted alkyl, R⁵⁴-substitutedor unsubstituted heteroalkyl, R⁵⁴-substituted or unsubstitutedcycloalkyl, R⁵⁴-substituted or unsubstituted heterocycloalkyl,R⁵⁴-substituted or unsubstituted aryl, or R⁵⁴-substituted orunsubstituted heteroaryl.

R⁵⁴ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁵⁵-substituted or unsubstituted alkyl, R⁵⁵-substituted or unsubstitutedheteroalkyl, R⁵⁵-substituted or unsubstituted cycloalkyl,R⁵⁵-substituted or unsubstituted heterocycloalkyl, R⁵⁵-substituted orunsubstituted aryl, or R⁵⁵-substituted or unsubstituted heteroaryl.

R⁵⁵ independently is halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁵⁶-substituted or unsubstituted alkyl, R⁵⁶-substituted or unsubstitutedheteroalkyl, R⁵⁶-substituted or unsubstituted cycloalkyl,R⁵⁶-substituted or unsubstituted heterocycloalkyl, R⁵⁶-substituted orunsubstituted aryl, or R⁵⁶-substituted or unsubstituted heteroaryl.

In a further embodiment, R⁵⁷ is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R⁵⁸-substituted or unsubstituted alkyl, R⁵⁸-substitutedor unsubstituted heteroalkyl, R⁵⁸-substituted or unsubstitutedcycloalkyl, R⁵⁸-substituted or unsubstituted heterocycloalkyl,R⁵⁸-substituted or unsubstituted aryl, or R⁵⁸-substituted orunsubstituted heteroaryl.

R⁵⁸ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁵⁹-substituted or unsubstituted alkyl, R⁵⁹-substituted or unsubstitutedheteroalkyl, R⁵⁹-substituted or unsubstituted cycloalkyl,R⁵⁹-substituted or unsubstituted heterocycloalkyl, R⁵⁹-substituted orunsubstituted aryl, or R⁵⁹-substituted or unsubstituted heteroaryl.

R⁵⁹ independently is halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁶⁰-substituted or unsubstituted alkyl, R⁶⁰-substituted or unsubstitutedheteroalkyl, R⁶⁰-substituted or unsubstituted cycloalkyl,R⁶⁰-substituted or unsubstituted heterocycloalkyl, R⁶⁰-substituted orunsubstituted aryl, or R⁶⁰-substituted or unsubstituted heteroaryl.

In some embodiments, L² is in each instance, independently selected froma bond, —C(O)—, —C(O)N(R⁶¹)—, —C(O)O—, —S(O)_(g)— (i.e. —S—, —S(O)— or—S(O)₂), —S(O)₂N(R⁶¹)—, —O—, —N(R⁶¹)—, —N(R⁶¹)C(O)N(R⁶²)—,R⁶³-substituted or unsubstituted alkylene, R⁶³-substituted orunsubstituted heteroalkylene, R⁶³-substituted or unsubstitutedcycloalkylene, R⁶³-substituted or unsubstituted heterocycloalkylene,R⁶³-substituted or unsubstituted arylene, or R⁶³-substituted orunsubstituted heteroarylene.

R⁶³ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁶⁴-substituted or unsubstituted alkyl, R⁶⁴-substituted or unsubstitutedheteroalkyl, R⁶⁴-substituted or unsubstituted cycloalkyl,R⁶⁴-substituted or unsubstituted heterocycloalkyl, R⁶⁴-substituted orunsubstituted aryl, or R⁶⁴-substituted or unsubstituted heteroaryl.

R⁶⁴ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁶⁵-substituted or unsubstituted alkyl, R⁶⁵-substituted or unsubstitutedheteroalkyl, R⁶⁵-substituted or unsubstituted cycloalkyl,R⁶⁵-substituted or unsubstituted heterocycloalkyl, R⁶⁵-substituted orunsubstituted aryl, or R⁶⁵-substituted or unsubstituted heteroaryl.

In some embodiments, R⁶¹ is independently hydrogen, halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, R⁶⁶-substituted or unsubstituted alkyl,R⁶⁶-substituted or unsubstituted heteroalkyl, R⁶⁶-substituted orunsubstituted cycloalkyl, R⁶⁶-substituted or unsubstitutedheterocycloalkyl, R⁶⁶-substituted or unsubstituted aryl, orR⁶⁶-substituted or unsubstituted heteroaryl.

R⁶⁶ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁶⁷-substituted or unsubstituted alkyl, R⁶⁷-substituted or unsubstitutedheteroalkyl, R⁶⁷-substituted or unsubstituted cycloalkyl,R⁶⁷-substituted or unsubstituted heterocycloalkyl, R⁶⁷-substituted orunsubstituted aryl, or R⁶⁷-substituted or unsubstituted heteroaryl.

R⁶⁷ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁶⁸-substituted or unsubstituted alkyl, R⁶⁸-substituted or unsubstitutedheteroalkyl, R⁶⁸-substituted or unsubstituted cycloalkyl,R⁶⁸-substituted or unsubstituted heterocycloalkyl, R⁶⁸-substituted orunsubstituted aryl, or R⁶⁸-substituted or unsubstituted heteroaryl.

In some embodiments, R⁶² is independently hydrogen, halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, R⁶⁹-substituted or unsubstituted alkyl,R⁶⁹-substituted or unsubstituted heteroalkyl, R⁶⁹-substituted orunsubstituted cycloalkyl, R⁶⁹-substituted or unsubstitutedheterocycloalkyl, R⁶⁹-substituted or unsubstituted aryl, orR⁶⁹-substituted or unsubstituted heteroaryl.

R⁶⁹ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁷⁰-substituted or unsubstituted alkyl, R⁷⁰-substituted or unsubstitutedheteroalkyl, R⁷⁰-substituted or unsubstituted cycloalkyl,R⁷⁰-substituted or unsubstituted heterocycloalkyl, R⁷⁰-substituted orunsubstituted aryl, or R⁷⁰-substituted or unsubstituted heteroaryl.

R⁷⁰ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁷¹-substituted or unsubstituted alkyl, R⁷¹-substituted or unsubstitutedheteroalkyl, R⁷¹-substituted or unsubstituted cycloalkyl,R⁷¹-substituted or unsubstituted heterocycloalkyl, R⁷¹-substituted orunsubstituted aryl, or R⁷¹-substituted or unsubstituted heteroaryl.

In some embodiments, R¹⁶, R¹⁹, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³,R⁴⁶, R⁴⁹, R⁵², R⁵⁶, R⁶⁰, R⁶⁵, R⁶⁸, and R⁷¹ are independently hydrogen,halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In some embodiments of any aspect of the compounds provide herein, aboronic ester is the compound of formula (VIII). R⁷², R⁷³, R⁷⁴, and R⁷⁵are as defined herein.

In some embodiments, R⁷² is independently hydrogen, halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, R⁷⁶-substituted or unsubstituted alkyl,R⁷⁶-substituted or unsubstituted heteroalkyl, R⁷⁶-substituted orunsubstituted cycloalkyl, R⁷⁶-substituted or unsubstitutedheterocycloalkyl, R⁷⁶-substituted or unsubstituted aryl, orR⁷⁶-substituted or unsubstituted heteroaryl.

R⁷⁶ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁷⁷-substituted or unsubstituted alkyl, R⁷⁷-substituted or unsubstitutedheteroalkyl, R⁷⁷-substituted or unsubstituted cycloalkyl,R⁷⁷-substituted or unsubstituted heterocycloalkyl, R⁷⁷-substituted orunsubstituted aryl, or R⁷⁷-substituted or unsubstituted heteroaryl.

R⁷⁷ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁷⁸-substituted or unsubstituted alkyl, R⁷⁸-substituted or unsubstitutedheteroalkyl, R⁷⁸-substituted or unsubstituted cycloalkyl,R⁷⁸-substituted or unsubstituted heterocycloalkyl, R⁷⁸-substituted orunsubstituted aryl, or R⁷⁸-substituted or unsubstituted heteroaryl.

In some embodiments, R⁷³ is independently hydrogen, halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, R⁷⁹-substituted or unsubstituted alkyl,R⁷⁹-substituted or unsubstituted heteroalkyl, R⁷⁹-substituted orunsubstituted cycloalkyl, R⁷⁹-substituted or unsubstitutedheterocycloalkyl, R⁷⁹-substituted or unsubstituted aryl, orR⁷⁹-substituted or unsubstituted heteroaryl.

R⁷⁹ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁸⁰-substituted or unsubstituted alkyl, R⁸⁰-substituted or unsubstitutedheteroalkyl, R⁸⁰-substituted or unsubstituted cycloalkyl,R⁸⁰-substituted or unsubstituted heterocycloalkyl, R⁸⁰-substituted orunsubstituted aryl, or R⁸⁰-substituted or unsubstituted heteroaryl.

R⁸⁰ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁸¹-substituted or unsubstituted alkyl, R⁸¹-substituted or unsubstitutedheteroalkyl, R⁸¹-substituted or unsubstituted cycloalkyl,R⁸¹-substituted or unsubstituted heterocycloalkyl, R⁸¹-substituted orunsubstituted aryl, or R⁸¹-substituted or unsubstituted heteroaryl.

In some embodiments, R⁷⁴ is independently hydrogen, halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, R⁸²-substituted or unsubstituted alkyl,R⁸²-substituted or unsubstituted heteroalkyl, R⁸²-substituted orunsubstituted cycloalkyl, R⁸²-substituted or unsubstitutedheterocycloalkyl, R⁸²-substituted or unsubstituted aryl, orR⁸²-substituted or unsubstituted heteroaryl.

R⁸² is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁸³-substituted or unsubstituted alkyl, R⁸³-substituted or unsubstitutedheteroalkyl, R⁸³-substituted or unsubstituted cycloalkyl,R⁸³-substituted or unsubstituted heterocycloalkyl, R⁸³-substituted orunsubstituted aryl, or R⁸³-substituted or unsubstituted heteroaryl.

R⁸³ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁸⁴-substituted or unsubstituted alkyl, R⁸⁴-substituted or unsubstitutedheteroalkyl, R⁸⁴-substituted or unsubstituted cycloalkyl,R⁸⁴-substituted or unsubstituted heterocycloalkyl, R⁸⁴-substituted orunsubstituted aryl, or R⁸⁴-substituted or unsubstituted heteroaryl.

In some embodiments, R⁷⁵ is independently hydrogen, halogen, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, R⁸⁵-substituted or unsubstituted alkyl,R⁸⁵-substituted or unsubstituted heteroalkyl, R⁸⁵-substituted orunsubstituted cycloalkyl, R⁸⁵-substituted or unsubstitutedheterocycloalkyl, R⁸⁵-substituted or unsubstituted aryl, orR⁸⁵-substituted or unsubstituted heteroaryl.

R⁸⁵ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁸⁶-substituted or unsubstituted alkyl, R⁸⁶-substituted or unsubstitutedheteroalkyl, R⁸⁶-substituted or unsubstituted cycloalkyl,R⁸⁶-substituted or unsubstituted heterocycloalkyl, R⁸⁶-substituted orunsubstituted aryl, or R⁸⁶-substituted or unsubstituted heteroaryl.

R⁸⁶ is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁸⁷-substituted or unsubstituted alkyl, R⁸⁷-substituted or unsubstitutedheteroalkyl, R⁸⁷-substituted or unsubstituted cycloalkyl,R⁸⁷-substituted or unsubstituted heterocycloalkyl, R⁸⁷-substituted orunsubstituted aryl, or R⁸⁷-substituted or unsubstituted heteroaryl.

In some embodiments, R⁷⁸, R⁸¹, R⁸⁴, and R⁸⁷ are independently hydrogen,halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂₅—NHC═(O)NHNH₂, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In some embodiments, R^(9A) is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(38A)-substituted or unsubstituted alkyl,R^(38A)-substituted or unsubstituted heteroalkyl, R^(38A)-substituted orunsubstituted cycloalkyl, R^(38A)-substituted or unsubstitutedheterocycloalkyl, R^(38A)-substituted or unsubstituted aryl, orR^(38A)-substituted or unsubstituted heteroaryl.

R^(38A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(39A)-substituted or unsubstituted alkyl, R^(39A)-substituted orunsubstituted heteroalkyl, R^(39A)-substituted or unsubstitutedcycloalkyl, R^(39A)-substituted or unsubstituted heterocycloalkyl,R^(39A)-substituted or unsubstituted aryl, or R^(39A)-substituted orunsubstituted heteroaryl.

R^(39A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(40A)-substituted or unsubstituted alkyl, R^(40A)-substituted orunsubstituted heteroalkyl, R^(40A)-substituted or unsubstitutedcycloalkyl, R^(40A)-substituted or unsubstituted heterocycloalkyl,R^(40A)-substituted or unsubstituted aryl, or R^(40A)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(10A) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(41A)-substituted or unsubstituted alkyl,R^(41A)-substituted or unsubstituted heteroalkyl, R^(41A)-substituted orunsubstituted cycloalkyl, R^(41A)-substituted or unsubstitutedheterocycloalkyl, R^(41A)-substituted or unsubstituted aryl, orR^(41A)-substituted or unsubstituted heteroaryl.

R^(41A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(42A)-substituted or unsubstituted alkyl, R^(42A)-substituted orunsubstituted heteroalkyl, R^(42A)-substituted or unsubstitutedcycloalkyl, R^(42A)-substituted or unsubstituted heterocycloalkyl,R^(42A)-substituted or unsubstituted aryl, or R^(42A)-substituted orunsubstituted heteroaryl.

R^(42A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(43A)-substituted or unsubstituted alkyl, R^(43A)-substituted orunsubstituted heteroalkyl, R^(43A)-substituted or unsubstitutedcycloalkyl, R^(43A)-substituted or unsubstituted heterocycloalkyl,R^(43A)-substituted or unsubstituted aryl, or R^(43A)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(11A) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(44A)-substituted or unsubstituted alkyl,R^(44A)-substituted or unsubstituted heteroalkyl, R^(44A)-substituted orunsubstituted cycloalkyl, R^(44A)-substituted or unsubstitutedheterocycloalkyl, R^(44A)-substituted or unsubstituted aryl, orR^(44A)-substituted or unsubstituted heteroaryl.

R^(44A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(45A)-substituted or unsubstituted alkyl, R^(45A)-substituted orunsubstituted heteroalkyl, R^(45A)-substituted or unsubstitutedcycloalkyl, R^(45A) substituted or unsubstituted heterocycloalkyl,R^(45A)-substituted or unsubstituted aryl, or R^(45A)-substituted orunsubstituted heteroaryl.

R^(45A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(46A)-substituted or unsubstituted alkyl, R^(46A)-substituted orunsubstituted heteroalkyl, R^(46A)-substituted or unsubstitutedcycloalkyl, R^(46A)-substituted or unsubstituted heterocycloalkyl,R^(46A)-substituted or unsubstituted aryl, or R^(46A)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(12A) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(47A)-substituted or unsubstituted alkyl,R^(47A)-substituted or unsubstituted heteroalkyl, R^(47A)-substituted orunsubstituted cycloalkyl, R^(47A)-substituted or unsubstitutedheterocycloalkyl, R^(47A)-substituted or unsubstituted aryl, orR^(47A)-substituted or unsubstituted heteroaryl.

R^(47A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(48A)-substituted or unsubstituted alkyl, R^(48A)-substituted orunsubstituted heteroalkyl, R^(48A)-substituted or unsubstitutedcycloalkyl, R^(48A) substituted or unsubstituted heterocycloalkyl,R^(48A)-substituted or unsubstituted aryl, or R^(48A)-substituted orunsubstituted heteroaryl.

R^(48A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(49A)-substituted or unsubstituted alkyl, R^(49A)-substituted orunsubstituted heteroalkyl, R^(49A)-substituted or unsubstitutedcycloalkyl, R^(49A)-substituted or unsubstituted heterocycloalkyl,R^(49A)-substituted or unsubstituted aryl, or R^(49A)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(13A) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂₅—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(50A)-substituted or unsubstituted alkyl,R^(50A)-substituted or unsubstituted heteroalkyl, R^(50A)-substituted orunsubstituted cycloalkyl, R^(50A)-substituted or unsubstitutedheterocycloalkyl, R^(50A)-substituted or unsubstituted aryl, orR^(50A)-substituted or unsubstituted heteroaryl.

R^(50A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(51A)-substituted or unsubstituted alkyl, R^(51A)-substituted orunsubstituted heteroalkyl, R^(51A)-substituted or unsubstitutedcycloalkyl, R^(51A) substituted or unsubstituted heterocycloalkyl,R^(51A)-substituted or unsubstituted aryl, or R^(51A)-substituted orunsubstituted heteroaryl.

R^(51A) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(52A)-substituted or unsubstituted alkyl, R^(52A)-substituted orunsubstituted heteroalkyl, R^(52A)-substituted or unsubstitutedcycloalkyl, R^(52A)-substituted or unsubstituted heterocycloalkyl,R^(52A)-substituted or unsubstituted aryl, or R^(52A)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(40A), R^(43A), R^(46A), R^(49A), and R^(52A) areindependently hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂₅—NHNH₂, —ONH₂, —NHC═(O)NHNH₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

In some embodiments, R^(7B) is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(32B)-substituted or unsubstituted alkyl,R^(32B)-substituted or unsubstituted heteroalkyl, R^(32B)-substituted orunsubstituted cycloalkyl, R^(32B)-substituted or unsubstitutedheterocycloalkyl, R^(32B)-substituted or unsubstituted aryl, orR^(32B)-substituted or unsubstituted heteroaryl.

R^(32B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(33B)-substituted or unsubstituted alkyl, R^(33B)-substituted orunsubstituted heteroalkyl, R^(33B)-substituted or unsubstitutedcycloalkyl, R^(33B) substituted or unsubstituted heterocycloalkyl,R^(33B)-substituted or unsubstituted aryl, or R^(33B)-substituted orunsubstituted heteroaryl.

R^(33B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(34B)-substituted or unsubstituted alkyl, R^(34B)-substituted orunsubstituted heteroalkyl, R^(34B)-substituted or unsubstitutedcycloalkyl, R^(34B)-substituted or unsubstituted heterocycloalkyl,R^(34B)-substituted or unsubstituted aryl, or R^(34B)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(8B) is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(35B)-substituted or unsubstituted alkyl,R^(35B)-substituted or unsubstituted heteroalkyl, R^(35B)-substituted orunsubstituted cycloalkyl, R^(35B)-substituted or unsubstitutedheterocycloalkyl, R^(35B)-substituted or unsubstituted aryl, orR^(35B)-substituted or unsubstituted heteroaryl.

R^(35B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(36B)-substituted or unsubstituted alkyl, R^(36B)-substituted orunsubstituted heteroalkyl, R^(36B)-substituted or unsubstitutedcycloalkyl, R^(36B) substituted or unsubstituted heterocycloalkyl,R^(36B)-substituted or unsubstituted aryl, or R^(36B)-substituted orunsubstituted heteroaryl.

R^(36B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(37B)-substituted or unsubstituted alkyl, R^(37B)-substituted orunsubstituted heteroalkyl, R^(37B)-substituted or unsubstitutedcycloalkyl, R^(37B)-substituted or unsubstituted heterocycloalkyl,R^(37B)-substituted or unsubstituted aryl, or R^(37B)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(9B) is hydrogen, halogen, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(38B)-substituted or unsubstituted alkyl,R^(38B)-substituted or unsubstituted heteroalkyl, R^(38B)-substituted orunsubstituted cycloalkyl, R^(38B)-substituted or unsubstitutedheterocycloalkyl, R^(38B)-substituted or unsubstituted aryl, orR^(38B)-substituted or unsubstituted heteroaryl.

R^(38B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(39B)-substituted or unsubstituted alkyl, R^(39B)-substituted orunsubstituted heteroalkyl, R^(39B)-substituted or unsubstitutedcycloalkyl, R^(39B)-substituted or unsubstituted heterocycloalkyl,R^(39B)-substituted or unsubstituted aryl, or R^(39B)-substituted orunsubstituted heteroaryl.

R^(39B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(40B)-substituted or unsubstituted alkyl, R^(40B)-substituted orunsubstituted heteroalkyl, R^(40B)-substituted or unsubstitutedcycloalkyl, R^(40B)-substituted or unsubstituted heterocycloalkyl,R^(40B)-substituted or unsubstituted aryl, or R^(40B)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(10B) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(41B)-substituted or unsubstituted alkyl,R^(41B)-substituted or unsubstituted heteroalkyl, R^(41B)-substituted orunsubstituted cycloalkyl, R^(41B)-substituted or unsubstitutedheterocycloalkyl, R^(41B)-substituted or unsubstituted aryl, orR^(41B)-substituted or unsubstituted heteroaryl.

R^(41B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(42B)-substituted or unsubstituted alkyl, R^(42B)-substituted orunsubstituted heteroalkyl, R^(42B)-substituted or unsubstitutedcycloalkyl, R^(42B)-substituted or unsubstituted heterocycloalkyl,R^(42B)-substituted or unsubstituted aryl, or R^(42B)-substituted orunsubstituted heteroaryl.

R^(42B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(43B)-substituted or unsubstituted alkyl, R^(43B)-substituted orunsubstituted heteroalkyl, R^(43B)-substituted or unsubstitutedcycloalkyl, R^(43B)-substituted or unsubstituted heterocycloalkyl,R^(43B)-substituted or unsubstituted aryl, or R^(43B)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(11B) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(44B)-substituted or unsubstituted alkyl,R^(44B)-substituted or unsubstituted heteroalkyl, R^(44B)-substituted orunsubstituted cycloalkyl, R^(44B)-substituted or unsubstitutedheterocycloalkyl, R^(44B)-substituted or unsubstituted aryl, orR^(44B)-substituted or unsubstituted heteroaryl.

R^(44B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(45B)-substituted or unsubstituted alkyl, R^(45B)-substituted orunsubstituted heteroalkyl, R^(45B)-substituted or unsubstitutedcycloalkyl, R^(45B) substituted or unsubstituted heterocycloalkyl,R^(45B)-substituted or unsubstituted aryl, or R^(45B)-substituted orunsubstituted heteroaryl.

R^(45B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(46B)-substituted or unsubstituted alkyl, R^(46B)-substituted orunsubstituted heteroalkyl, R^(46B)-substituted or unsubstitutedcycloalkyl, R^(46B)-substituted or unsubstituted heterocycloalkyl,R^(46B)-substituted or unsubstituted aryl, or R^(46B)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(12B) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(47B)-substituted or unsubstituted alkyl,R^(47B)-substituted or unsubstituted heteroalkyl, R^(47B)-substituted orunsubstituted cycloalkyl, R^(47B)-substituted or unsubstitutedheterocycloalkyl, R^(47B)-substituted or unsubstituted aryl, orR^(47B)-substituted or unsubstituted heteroaryl.

R^(47B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R⁴⁰-substituted or unsubstituted alkyl, R^(48B)-substituted orunsubstituted heteroalkyl, R^(48B)-substituted or unsubstitutedcycloalkyl, R^(48B) substituted or unsubstituted heterocycloalkyl,R^(48B)-substituted or unsubstituted aryl, or R^(48B)-substituted orunsubstituted heteroaryl.

R^(48B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(49B)-substituted or unsubstituted alkyl, R^(49B)-substituted orunsubstituted heteroalkyl, R^(49B)-substituted or unsubstitutedcycloalkyl, R^(49B)-substituted or unsubstituted heterocycloalkyl,R^(49B)-substituted or unsubstituted aryl, or R^(49B)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(13B) is hydrogen, halogen, —CN, —OH, —NH₂,—COOH, —CONH₂₅—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, R^(50B)-substituted or unsubstituted alkyl,R^(50B)-substituted or unsubstituted heteroalkyl, R^(50B)-substituted orunsubstituted cycloalkyl, R^(50B)-substituted or unsubstitutedheterocycloalkyl, R^(50B)-substituted or unsubstituted aryl, orR^(50B)-substituted or unsubstituted heteroaryl.

R^(50B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(51B)-substituted or unsubstituted alkyl, R^(51B)-substituted orunsubstituted heteroalkyl, R^(51B)-substituted or unsubstitutedcycloalkyl, R^(51B) substituted or unsubstituted heterocycloalkyl,R^(51B)-substituted or unsubstituted aryl, or R^(51B)-substituted orunsubstituted heteroaryl.

R^(51B) is independently halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,R^(52B)-substituted or unsubstituted alkyl, R^(52B)-substituted orunsubstituted heteroalkyl, R^(52B)-substituted or unsubstitutedcycloalkyl, R^(52B)-substituted or unsubstituted heterocycloalkyl,R^(52B)-substituted or unsubstituted aryl, or R^(52B)-substituted orunsubstituted heteroaryl.

In some embodiments, R^(40B), R^(43B), R^(46B), R^(49B), and R^(52B) areindependently hydrogen, halogen, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂₅—NHNH₂, —ONH₂, —NHC═(O)NHNH₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

In some embodiments, the compound is any one or more of the compounds inTable 1 below:

TABLE 1

In some embodiments, a compound selected from the compounds listed abovemay be administered or used in a method selected from any of the methodsdescribed herein or included in any pharmaceutical composition providedherein.

III. Methods

In another aspect, a method of treating a disease in a patient in needof such treatment is provided. The method including administering atherapeutically effective amount of an oxidatively-sensitive prodrug tothe patient. The oxidatively sensitive prodrug may be a compound offormula I, Ia, II, III, IIIa or IV (including embodiments thereof). Insome embodiments, the oxidatively-sensitive prodrug forms a drug uponexposure to an oxidative compound. In some embodiments, the compound offormula I may form a drug having the formula A-OH. In some embodiments,the compound of formula II may form a drug having the formula B—OH. Insome embodiments, the compound of formula III may form a drug having theformula C-L¹-X¹—H. In some embodiments, the compound of formula IIIa mayform a drug having the formula C-L¹-X¹—H. L¹ and X¹ are as definedherein, including embodiments. In some embodiments, the compound offormula IV may form a drug having the formula D-OH.

In an embodiment, the oxidatively-sensitive prodrug includes a drugmoiety covalently linked to an oxidatively-sensitive prodrug moiety. Inone embodiment, the drug moiety includes a moiety known to be useful fortreating the disease for which the prodrug is administered. In oneembodiment, the drug moiety may form a drug known to be useful fortreating the disease for which the prodrug is administered incombination with a chemical moiety remaining or formed after the prodrugmoiety reacts with an oxidative compound. Known drugs useful in specificdiseases are discussed in the Physicians' Desk Reference as being usefulfor treating the disease (hardcopy (e.g. 2011 Physican's Desk ReferenceISBN-13: 9781563637803), electronic (e.g. 2011 PDR on CD-ROM), or onlineversion). In some embodiments, a drug is known to be useful for treatinga disease because the drug has been approved by the U.S. FDA, or anequivalent authority in a different country, for use in treating thedisease. In another embodiment, following administration of theoxidatively-sensitive prodrug to the patient, the drug moiety forms adrug that is known to be useful for treating the disease for which theoxidatively-sensitive prodrug was administered to the patient. The drugmay be known to be useful for a disease because it has been approved totreat that disease by the U.S. FDA or a corresponding authority in adifferent country. In a further embodiment, the method includes allowingthe oxidatively-sensitive prodrug to react with a reactive oxygenspecies after administering the oxidatively-sensitive prodrug andthereby forming the drug from the drug moiety.

In some embodiments, the oxidatively-sensitive prodrug reacts with areactive oxygen species at a location within the patient associated withthe disease for which the prodrug is administered. In some embodiments,the drug moiety forms the drug primarily at a location associated withthe disease. In some embodiments, primarily formed means more drug formsat a location associated with the disease than any other single locationwithin the patient. In some embodiments, the drug forms from the drugmoiety at the location associated with the occurrence of a stroke. Insome embodiments, the drug forms from the drug moiety at a location ofischemia. In some embodiments, the drug forms from the drug moiety at alocation of reperfusion injury. In some embodiments, the drug forms fromthe drug moiety at a location of stroke. In some embodiments, the drugforms from the drug moiety at a location of arthritis. In someembodiments, the drug forms from the drug moiety at a location of aninflammatory disease. In some embodiments, the drug forms from the drugmoiety at a location of rheumatoid arthritis. In some embodiments, thedrug forms from the drug moiety at a location of cancer. In someembodiments, the drug forms from the drug moiety at a location where atumor is located. In some embodiments, the drug forms in the brain. Thedrug may form near the blood brain barrier.

In some embodiments, the method includes administration of the prodrugwithin 1 hour of a stroke. In some embodiments, the method includesadministration of the prodrug within 2 hours of a stroke. In someembodiments, the method includes administration of the prodrug within 3hours of a stroke. In some embodiments, the method includesadministration of the prodrug within 5 hours of a stroke. In someembodiments, the method includes administration of the prodrug within 12hours of a stroke. In some embodiments, the method includesadministration of the prodrug within 24 hours of a stroke. In someembodiments, the method includes administration of the prodrug within 36hour of a stroke. In some embodiments, the method includesadministration of the prodrug within 48 hours of a stroke.

In some embodiments, the drug formed from the drug moiety of theoxidatively-sensitive prodrug includes or is a metal binding moiety. Insome embodiments, the drug includes or is a zinc binding moiety.

In some embodiments, the oxidatively-sensitive prodrug may be a compoundset forth herein (e.g. a compound of formula I, Ia, II, III, IIIa, orIV).

In a further embodiment, the method includes an oxidatively-sensitiveprodrug, which is a compound of the formula I, Ia, II, III, IIIa, or IVabove and embodiments thereof.

In another aspect, a method is provided for inhibiting a metalloprotein(e.g. inhibiting metalloprotein activity). The method may includecontacting the metalloprotein with a metal binding moiety formed fromthe reaction of an oxidatively-sensitive prodrug and an oxidativecompound (e.g. a reactive oxygen species). The oxidatively-sensitiveprodrug may be a compound of formula I, Ia, II, III, IIIa, or IV(including embodiments thereof). In some embodiments, theoxidatively-sensitive prodrug forms a drug upon exposure to an oxidativecompound (e.g. in combination with a chemical moiety as describedabove). In some embodiments, the compound of formula I may form a drughaving the formula A-OH. In some embodiments, the compound of formula IImay form a drug having the formula B—OH. In some embodiments, thecompound of formula III may form a drug having the formula C-L¹-X¹—H. Insome embodiments, the compound of formula IIIa may form a drug havingthe formula C-L¹-X¹—H. L¹ and X¹ are as defined herein, includingembodiments. In some embodiments, the compound of formula IV may form adrug having the formula D-OH.

In further embodiments, the metalloprotein is a metalloenzyme. In someembodiments, the metalloprotein is a metalloprotease. In someembodiments, the metalloprotease is a matrix metalloprotease. In someembodiments, the metalloprotease is associated with stroke. In someembodiments, the metalloprotease is associated with breakdown of theblood brain barrier. In some embodiments, the metalloprotease isactivated by an ROS. In some embodiments, the metalloprotease is MMP8.In some embodiments, the metalloprotease is MMP9. In some embodiments,the metalloprotease is MMP12. In some embodiments, the metalloprotein iswithin an organism. In some embodiments, the metalloprotein is within ahuman. In some embodiments, the metalloprotein is within a mammal. Insome embodiments, the metalloprotein is within a cell. In someembodiments, the metalloprotein is in the extracellular matrix of anorganism. In some embodiments, the metalloprotein is outside of a cellin an organism. In some embodiments, the metalloprotein is within areaction vessel. In some embodiments, the reaction vessel is not anorganism. In some embodiments, the reaction vessel is plastic, metal, agel, paper, tissue, glass, an alloy, fiber, or a combination of two ormore of the aforementioned substances. In some embodiments, the reactionvessel is inanimate (e.g. not an organism or cell).

In another aspect, a method is provided for inhibiting the activity of ametalloprotein, the method including contacting the metalloprotein withan oxidatively-sensitive prodrug The oxidatively-sensitive prodrug maybe a compound of formula I, Ia, II, III, IIIa, or IV (includingembodiments thereof). in the presence of an oxidative compound. In someembodiments, the oxidatively-sensitive prodrug forms a drug uponexposure to an oxidative compound. In some embodiments, the compound offormula I may form a drug having the formula A-OH. In some embodiments,the compound of formula II may form a drug having the formula B—OH. Insome embodiments, the compound of formula III may form a drug having theformula C-L¹-X¹—H. In some embodiments, the compound of formula IIIa mayform a drug having the formula C-L¹-X¹—H. L¹ and X¹ are as definedherein, including embodiments. In some embodiments, the compound offormula IV may form a drug having the formula D-OH. In some embodiment,the oxidative compound is an ROS. In some embodiments, the ROS ishydrogen peroxide. In some embodiments, the drug is a metal bindingcompound. In some embodiments, the metal binding compound is a zincbinding compound.

In some embodiments, a method selected from the methods described hereinincludes a compound selected from Table 1. In some embodiments, a methodof treating a disease in a patient in need of such treatment, includesadministering a therapeutically effective amount of anoxidatively-sensitive prodrug to the patient. In some embodiments, theoxidatively-sensitive prodrug is selected from the oxidatively-sensitiveprodrugs described herein. In some embodiments, a method of inhibitingthe activity of a protein includes contacting the protein with a drugformed from the reaction of an oxidatively-sensitive prodrug and areactive oxygen species. In some embodiments, the protein is a metalbinding protein and the drug is a metal binding compound.

In some embodiments of a method of treating a disease in a patient inneed of such treatment, the method includes forming a drug. In someembodiments, a method includes forming a drug from a compound of formula(V). In some embodiments, a method includes forming a drug by contactinga compound of formula (V) with a glycosidase enzyme. In someembodiments, a method includes treating a disease associated withincreased expression of one or more glycosidase enzymes.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,the certain methods presented herein successfully treat cancer bydecreasing the incidence of cancer and or causing remission of cancer.The term “treating,” and conjugations thereof, include prevention of aninjury, pathology, condition, or disease.

An “effective amount” is an amount sufficient to contribute to thetreatment, prevention, or reduction of a symptom or symptoms of adisease. An “effective amount” may also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug is an amountof a drug that, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a prodrug with a protein, anoxidatively-sensitive prodrug with a protein, an oxidatively-sensitiveprodrug with a metalloprotein, an oxidatively-sensitive prodrug with anROS, a prodrug comprising a carbohydrate moiety and a hydrolase capableof cleaving the bond between the carbohydrate moiety and thenon-carbohydrate moiety of the prodrug, a drug with a protein.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein (e.g. a metalloprotein, metalloenzyme, metalloprotease) relativeto the activity or function of the protein in the absence of theinhibitor. Thus, inhibition includes, at least in part, partially ortotally blocking stimulation, decreasing, preventing, or delayingactivation, or inactivating, desensitizing, or down-regulating signaltransduction or enzymatic activity. Similarly an “inhibitor” is acompound that inhibits metalloenzyme activity, e.g., by binding,partially or totally block stimulation, decrease, prevent, or delayactivation, or inactivate, desensitize, or down-regulate signaltransduction or enzymatic activity.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals and othernon-mammalian animals.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with the compounds ormethods provided herein. In some embodiments, the disease is a diseaserelated to (e.g. caused by) an oxidative compound such as reactiveoxygen species (e.g. Alzheimer's disease, Parkinson's disease,osteoporosis, inflammatory diseases, osteoarthritis, rheumatoidarthritis, stroke, aneurysm, brain aneurysm, cerebral aneurysm, brainattack, cerebrovascular accident, ischemia, thrombosis, arterialembolism, hemorrhage, transient ischemic attack, embolism, systemichypoperfusion, venous thrombosis, arthritis, reperfusion injury, acne,eczema, rosacea, sun damage, or wrinkles.). Examples of diseases,disorders, or conditions include, but are not limited to, cancer,cardiovascular disease, hypertension, Syndrome X, depression, anxiety,glaucoma, human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS), neurodegeneration, Alzheimer'sdisease, Parkinson's disease, cognition enhancement, Cushing's Syndrome,Addison's Disease, osteoporosis, frailty, muscle frailty, inflammatorydiseases, osteoarthritis, rheumatoid arthritis, asthma and rhinitis,adrenal function-related ailments, viral infection, immunodeficiency,immunomodulation, autoimmune diseases, allergies, wound healing,compulsive behavior, multi-drug resistance, addiction, psychosis,anorexia, cachexia, post-traumatic stress syndrome, post-surgical bonefracture, medical catabolism, major psychotic depression, mild cognitiveimpairment, psychosis, dementia, hyperglycemia, stress disorders,antipsychotic induced weight gain, delirium, cognitive impairment indepressed patients, cognitive deterioration in individuals with Down'ssyndrome, psychosis associated with interferon-alpha therapy, chronicpain, pain associated with gastroesophageal reflux disease, postpartumpsychosis, postpartum depression, neurological disorders in prematureinfants, migraine headaches, stroke, aneurysm, brain aneurysm, cerebralaneurysm, brain attack, cerebrovascular accident, ischemia, thrombosis,arterial embolism, hemorrhage, transient ischemic attack, anemia,embolism, systemic hypoperfusion, venous thrombosis, arthritis,reperfusion injury, skin diseases or conditions, acne, acne vulgaris,keratosis pilaris, acute, promyelocytic leukemia, baldness, acnerosacea, harlequin ichthyosis, xeroderma pigmentosum, keratoses,neuroblastoma, fibrodysplasia ossificans progressive, eczema, rosacea,sun damage, wrinkles, or cosmetic conditions. In some instances,“disease” or “condition” refer to cancer. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma.

As used herein, the term “autoimmune disease” refers to a disease orcondition in which a subject's immune system irregularly responds to oneor more components (e.g. biomolecule, protein, cell, tissue, organ,etc.) of the subject. In some embodiments, an autoimmune disease is acondition in which the subject's immune system irregularly reacts to oneor more components of the subject as if such components were not self.Exemplary autoimmune diseases that may be treated with a compound ormethod provided herein include Acute Disseminated Encephalomyelitis(ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison'sdisease, Agammaglobulinemia, Asthma, Allergic asthma, Allergic rhinitis,Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBMnephritis, Antiphospholipid syndrome (APS), Arthritis, Autoimmuneaplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis,Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune innerear disease (AIED), Autoimmune myocarditis, Autoimmune pancreatitis,Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP),Autoimmune thyroid disease, Axonal & neuronal neuropathies, Balodisease, Behcet's disease, Bullous pemphigoid, Cardiomyopathy, Castlemandisease, Celiac sprue, Chagas disease, Chronic inflammatorydemyelinating polyneuropathy (CIDP), Chronic recurrent multifocalosteomyelitis (CRMO), Churg-Strauss syndrome, Cicatricialpemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome,Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis,CREST disease, Essential mixed cryoglobulinemia, Demyelinatingneuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease(neuromyelitis optica), Discoid lupus, Dressler's syndrome,Endometriosis, Eosinophilic fasciitis, Erythema nodosum, Experimentalallergic encephalomyelitis, Evans syndrome, Fibrosing alveolitis, Giantcell arteritis (temporal arteritis), Glomerulonephritis, Goodpasture'ssyndrome, Graves' disease, Grave's ophthalmopathy, Guillain-Barresyndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolyticanemia, Henoch-Schonlein purpura, Herpes gestationis,Hypogammaglobulinemia, Ichthyosis, Idiopathic thrombocytopenic purpura(ITP), IgA nephropathy, IgG4-related sclerosing disease,Immunoregulatory lipoproteins, Inclusion body myositis, Inflammatorybowel disease, Insulin-dependent diabetes (type 1), Interstitialcystitis, Juvenile arthritis, Juvenile diabetes, Kawasaki syndrome,Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus,Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD),Lupus (SLE), Lyme disease, chronic, Meniere's disease, Microscopicpolyangiitis, Mixed connective tissue disease (MCTD), Mooren's ulcer,Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis,Myositis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia,Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism,PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated withStreptococcus), Paraneoplastic cerebellar degeneration, Paroxysmalnocturnal hemoglobinuria (PNH), Parry Romberg syndrome,Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis),Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis,Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, &III autoimmune polyglandular syndromes, Polymyalgia rheumatic,Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomysyndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primarysclerosing cholangitis, Psoriasis, Psoriatic, arthritis, Idiopathicpulmonary fibrosis, Pyoderma gangrenous, Pure red cell aplasia, Raynaudsphenomenon, Reflex sympathetic dystrophy, Reiter's syndrome, Relapsingpolychondritis, Restless legs syndrome, Retroperitoneal Fibrosis,Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome,Scleritis, Scleroderma, Sjogren's syndrome, Sperm & testicularautoimmunity, Stiff person syndrome, Subacute bacterial endocarditis(SBE), Susac's syndrome, Sympathetic ophthalmia, Takayasu's arteritis,Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP),Tolosa-Hunt syndrome, Transverse myelitis, Ulcerative colitis,Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis,Vesiculobullous dermatosis, Vitiligo, or Wegener's granulomatosis.

As used herein, the term “inflammatory disease” refers to any diseasecharacterized by abnormal inflammation. Exemplary inflammatory diseasesthat may be treated with a compound or method provided herein includearthritis, rheumatoid arthritis, psoriatic arthritis, juvenileidiopathic arthritis, multiple sclerosis, systemic lupus erythematosus(SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitustype 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto'sthyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet'sdisease, Crohn's disease, ulcerative colitis, bullous pemphigoid,sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory boweldisease, Addison's disease, Vitiligo, asthma, or allergic asthma.

As used herein, the term “cardiovascular disease” refers to a disease orcondition affecting the heart or blood vessels. In embodiments,cardiovascular disease includes diseases caused by or exacerbated byatherosclerosis. Exemplary cardiovascular diseases that may be treatedwith a compound or method provided herein include Alcoholiccardiomyopathy, Coronary artery disease, Congenital heart disease,Arrhythmogenic right ventricular cardiomyopathy, Restrictivecardiomyopathy, Noncompaction Cardiomyopathy, diabetes mellitus,hypertension, hyperhomocysteinemia, hypercholesterolemia,Atherosclerosis, Ischemic heart disease, Heart failure, Cor pulmonale,Hypertensive heart disease, Left ventricular hypertrophy, Coronary heartdisease, (Congestive) heart failure, Hypertensive cardiomyopathy,Cardiac arrhythmias, Inflammatory heart disease, Endocarditis,Inflammatory cardiomegaly, Myocarditis, Valvular heart disease, stroke,or myocardial infarction. In some embodiments, treating a cardiovasculardisease includes treating a condition or symptom caused by acardiovascular disease. A non-limiting example of such a treatment istreating complications due to a myocardial infarction, after themyocardial infarction has occurred.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals, including leukemia,carcinomas and sarcomas. Exemplary cancers that may be treated with acompound or method provided herein include cancer of the brain, breast,cervix, colon, head & neck, liver, kidney, lung, non-small cell lung,melanoma, mesothelioma, ovary, sarcoma, stomach, uterus orMedulloblastoma. Additional examples include, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, cancer, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniformi carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

In some embodiments, a disease or condition capable of being treatedwith the compounds or methods provided herein, include reactive oxygenspecies generating diseases or conditions, or oxidative compoundgenerating diseases or conditions, either of which may include, forexample, neurodegeneration, Alzheimer's disease, Parkinson's disease,osteoporosis, frailty, muscle frailty, inflammatory diseases,osteoarthritis, rheumatoid arthritis, asthma and rhinitis, dementia,delirium, cognitive impairment in depressed patients, stroke, aneurysm,brain aneurysm, cerebral aneurysm, brain attack, cerebrovascularaccident, ischemia, thrombosis, arterial embolism, hemorrhage, transientischemic attack, anemia, embolism, systemic hypoperfusion, venousthrombosis, arthritis, and reperfusion injury, acne, eczema, rosacea,sun damage, or wrinkles.

The term “cosmetic condition”, as used herein, includes diseases orconditions that may be treated with a compound or method providedherein, including, but not limited to, eczema, rosacea, acne, sundamage, wrinkles, acne vulgaris, keratosis pilaris, acute, promyelocyticleukemia, baldness, acne rosacea, harlequin ichthyosis, xerodermapigmentosum, or keratoses. The terms “cosmetic condition”,“dermatological condition”, and “skin condition” are usedinterchangeably.

IV. Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound provided herein (e.g., a compound offormula I, Ia, II, III, IIIa, IV, V, including the reactive oxygenspecies activatable prodrug, carbohydrate comprising prodrug, boronicacid comprising prodrug, boronic ester comprising prodrug, benzyl ethercomprising prodrug, metal binding moiety containing prodrug, zincbinding moiety containing prodrug) in combination with apharmaceutically acceptable carrier. The pharmaceutical compositionsinclude optical isomers, diastereomers, or pharmaceutically acceptablesalts of the modulators disclosed herein. The compound included in thepharmaceutical composition may be covalently attached to a carriermoiety, as described above. Alternatively, the compound included in thepharmaceutical composition is not covalently linked to a carrier moiety.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine. and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The compounds of the invention can be administered alone or can becoadministered to the patient. Coadministration is meant to includesimultaneous or sequential administration of the compounds individuallyor in combination (more than one compound). Thus, the preparations canalso be combined, when desired, with other active substances (e.g. toreduce metabolic degradation).

The compounds of the present invention can be prepared and administeredin a wide variety of oral, parenteral and topical dosage forms. Oralpreparations include tablets, pills, powder, dragees, capsules, liquids,lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitablefor ingestion by the patient. The compounds of the present invention canalso be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally. Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally. Itis also envisioned that multiple routes of administration (e.g.,intramuscular, oral, transdermal) can be used to administer thecompounds of the invention. Accordingly, the present invention alsoprovides pharmaceutical compositions comprising a pharmaceuticallyacceptable excipient and one or more compounds of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substance, that may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component (e.g. a compound provided herein. Intablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5% to 70% of the active compound.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds of the invention are injectable, sterilesolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. In particular, carriersfor parenteral administration include aqueous solutions of dextrose,saline, pure water, ethanol, glycerol, propylene glycol, peanut oil,sesame oil, polyoxyethylene-block polymers, and the like. Ampules areconvenient unit dosages. The compounds of the invention can also beincorporated into liposomes or administered via transdermal pumps orpatches. Pharmaceutical admixtures suitable for use in the presentinvention are well-known to those of skill in the art and are described,for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co.,Easton, Pa.) and WO 96/05309, the teachings of both of which are herebyincorporated by reference.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecithin), a condensation productof an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate),a condensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethylene oxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensationproduct of ethylene oxide with a partial ester derived from fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).The aqueous suspension can also contain one or more preservatives suchas ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can contain a thickening agent, such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents can be added to provide apalatable oral preparation, such as glycerol, sorbitol or sucrose. Theseformulations can be preserved by the addition of an antioxidant such asascorbic acid. As an example of an injectable oil vehicle, see Minto, J.Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulationsof the invention can also be in the form of oil-in-water emulsions. Theoily phase can be a vegetable oil or a mineral oil, described above, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening agents and flavoring agents, as inthe formulation of syrups and elixirs. Such formulations can alsocontain a demulcent, a preservative, or a coloring agent.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84and P-103; cyclodextrin; polyoxyl 35 castor oil; or other agents knownto those skilled in the art. Such co-solvents are typically employed ata level between about 0.01% and about 2% by weight.

Viscosity greater than that of simple aqueous solutions may be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, combinations of the foregoing, and other agents known tothose skilled in the art. Such agents are typically employed at a levelbetween about 0.01% and about 2% by weight. Determination of acceptableamounts of any of the above adjuvants is readily ascertained by oneskilled in the art.

The compositions of the present invention may additionally includecomponents to provide sustained release and/or comfort. Such componentsinclude high molecular weight, anionic mucomimetic polymers, gellingpolysaccharides and finely-divided drug carrier substrates. Thesecomponents are discussed in greater detail in U.S. Pat. Nos. 4,911,920;5,403,841; 5,212,162; and 4,861,760. The entire contents of thesepatents are incorporated herein by reference in their entirety for allpurposes.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., modulating the activity of a targetmolecule (e.g. metalloprotein or metalloprotease), and/or reducing,eliminating, or slowing the progression of disease symptoms.Determination of a therapeutically effective amount of a compound of theinvention is well within the capabilities of those skilled in the art,especially in light of the detailed disclosure herein.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated (e.g., stroke), kind of concurrent treatment,complications from the disease being treated or other health-relatedproblems. Other therapeutic regimens or agents can be used inconjunction with the methods and compounds of Applicants' invention.Adjustment and manipulation of established dosages (e.g., frequency andduration) are well within the ability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. In one embodiment, the dosage range is 0.001% to 10% w/v. Inanother embodiment, the dosage range is 0.1% to 5% w/v.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The ratio between toxicity and therapeutic effect for a particularcompound is its therapeutic index and can be expressed as the ratiobetween LD₅₀ (the amount of compound lethal in 50% of the population)and ED₅₀ (the amount of compound effective in 50% of the population).Compounds that exhibit high therapeutic indices are preferred.Therapeutic index data obtained from cell culture assays and/or animalstudies can be used in formulating a range of dosages for use in humans.The dosage of such compounds preferably lies within a range of plasmaconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. See, e.g. Fingl etal., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, p. 1, 1975.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition and theparticular method in which the compound is used.

V. Administration

The compositions of the present invention can be delivered bytransdermally, by a topical route, formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols.

The compositions of the present invention can also be delivered asmicrospheres for slow release in the body. For example, microspheres canbe administered via intradermal injection of drug-containingmicrospheres, which slowly release subcutaneously (see Rao, J. BiomaterSci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gelformulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, asmicrospheres for oral administration (see, e.g., Eyles, J. Pharm.Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routesafford constant delivery for weeks or months.

The pharmaceutical compositions of the present invention can be providedas a salt and can be formed with many acids, including but not limitedto hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic,etc. Salts tend to be more soluble in aqueous or other protonic solventsthat are the corresponding free base forms. In other cases, thepreparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2%sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combinedwith buffer prior to use.

In another embodiment, the compositions of the present invention areuseful for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the formulationcan be a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension can be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the formulations of the compositions of thepresent invention can be delivered by the use of liposomes which fusewith the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the compositions of the present invention into the targetcells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306,1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J.Hosp. Pharm. 46:1576-1587, 1989).

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating adisease associated with generation of reactive oxygen species (e.g.stroke), or with adjunctive agents that may not be effective alone, butmay contribute to the efficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another.

In some embodiments, a pharmaceutical composition as described hereinincludes a compound selected from the compounds of Table 1.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1 Exemplary Syntheses Related to Carbohydrate ZBGs s

General Methods. All chemicals were purchased from commercial suppliers(Aldrich, Alfa Aesar, TCI, or Fisher) and used as is. β-glucosidase (EC3.2.1.21) from almonds was purchased from Fluka. 1H and 13C NMR spectrawere recorded on either a Varian FT-NMR instrument running at 400 MHz or500 MHz, or a 500 MHz Jeol instrument at the Department of Chemistry andBiochemistry, University of California, San Diego. Mass spectrometry wasperformed at the Small Molecule Mass Spectrometry Facility in theDepartment of Chemistry and Biochemistry at the University ofCalifornia, San Diego. Elemental analysis was performed by NuMegaResonance Labs, San Diego.

1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-pyridin-2(1H)-one (2a).1-Hydroxypyridine-2(1H)-one (1, 0.50 g, 4.5 mmol) was dissolved in 10 mLof dichloromethane. To this was added 1-bromo-α-D-glucose tetraacetate(0.74 g, 1.8 mmol) and tetrabutylammonium bromide (0.58 g, 1.8 mmol).After heating to 35° C., 10 mL of 1.0 M NaOH was added. Theheterogeneous reaction mixture was vigorously stirred for 3 h. Aftercooling to room temperature, the reaction was diluted with 20 mL ofethyl acetate then washed 2× with 1.0 M NaOH (20 mL) followed by waterand brine. The organic layer was dried over MgSO₄, filtered, andconcentrated for silica gel column purification in 2% MeOH in CH₂Cl₂yielding an off-white solid in 29% yield (0.23 g). ¹H NMR (500 MHz,CDCl₃) δ=7.51 (dd, J₁=6.9 Hz, J₂=1.8 Hz, 1H), 7.28 (dt, J₁=8.6 Hz,J₂=2.9 Hz, 1H), 6.60 (dd, J₁=9.8 Hz, J₂=1.8 Hz, 1H), 6.04 (dt, J₁=6.9Hz, J₂=1.7 Hz, 1H), 5.29 (t, J=9.2 Hz, 1H), 5.21 (d, J=8.6 Hz, 1H), 5.16(t, J=9.8 Hz, 1H), 5.09 (t, J=9.8 Hz, 1H), 4.26 (dd, J₁=12.6 Hz, J₂=5.2Hz, 1H, CHCHaHbOAc), 4.09 (dd, J₁=12.1H, J₂=2.3 Hz, 1H, CHCHaHbOAc),3.68 (dq, J₁=10.3 Hz, J₂=2.3 Hz, 1H, CHCHaHbOAc), 2.16 (s, 3H), 2.02 (s,3H), 2.00 (s, 6H). 13C NMR (125 MHz, CDCl3) δ=170.5, 170.1, 169.9,169.5, 157.9, 139.3, 137.8, 122.8, 104.3, 103.5, 77.5, 72.3, 69.3, 68.0,61.4, 20.7. ESI-MS(+): m/z 441.77[M+H]+, 464.06[M+Na]+.

1-Hydroxypyridin-2(1H)-one-β-D-glucopyranoside (2). 2a (0.21 g, 0.48mmol) was dissolved in 10 mL of dry MeOH. To this was added 0.33 mL(1.42 mmol) of NaOMe (25% in MeOH). The reaction was left stirring for 3h at room temperature before the addition of −100 mg cation exchangeresin (Biorad AG-50W-X8, H+ form) that was allowed to stir for anadditional 10 min. The reaction mixture was filtered and the solventswere evaporated for column purification eluting with 10% MeOH in EtOAc.2 was collected as a white solid in 50% yield (0.063 g, 0.23 mmol). 1HNMR (500 MHz, CD3OD) δ=7.97 (dd, J1=6.9 Hz, J2=2.3 Hz, 1H), 7.53 (dt,J1=8.6 Hz, 2.3 Hz, 1H), 6.67 (dd, J1=9.2 Hz, J2=1.7 Hz, 1H), 6.34 (dt,J1=6.9 Hz, J2=1.7 Hz, 1H), 4.99 (d, J=8.0 Hz, 1H), 3.81 (dd, J1=12.1 Hz,J2=1.7 Hz, 1H, CHCHaHbOH), 3.68 (dd, J1=12.0 Hz, J2=4.6 Hz, 1H,CHCHaHbOH), 3.44 (t, J=8.6 Hz, 1H), 3.37-3.30 (m, overlapping peaks,3H). 13C NMR (125 MHz, CD3OD) δ=152.9, 140.6, 138.7, 120.9, 107.4,106.2, 77.4, 76.2, 72.1, 69.2, 60.8. APCI-MS(+): m/z 273.94 [M+H]+.Anal. calcd for C11H15N07: C, 48.35; H, 5.53; N, 5.13. Found: C, 47.95;H, 5.90; N, 4.86.

2-Methyl-4H-pyran-4-one-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside)(4a). The synthesis of 4a was accomplished following the same procedureas that for 2a using 3-hydroxy-2-methyl-4-pyrone (1.0 g, 7.9 mmol),1-bromo-α-D-glucose tetraacetate (1.3 g, 3.2 mmol) andtetrabutylammonium bromide (1.02 g, 3.2 mmol) in 20 mL of CH2Cl2 and 20mL of 1 M NaOH at 35° C. 4a was collected as an off white solid in 28%yield (0.401 g, 0.88 mmol). 1H NMR (500 MHz, CDCl3) δ=7.62 (d, J=5.7 Hz,1H), 6.32 (d, J=5.8 Hz, 1H), 5.32 (d, J=8.1 Hz, 1H), 5.27 (t, J=9.2 Hz,1H), 5.16 (t, J=8.0 Hz, 1H), 5.09 (t, J=9.8 Hz, 1H), 4.17 (dd, J1=12.0Hz, J2=4.6 Hz, 1H, CHCHaHbOAc), 4.10 (dd, J1=12.6H, J2=2.3 Hz, 1H,CHCHaHbOAc), dq (3.63, J1=10.4 Hz, J2=1.7 Hz, 1H, CHCHaHbOAc), 2.29 (s,3H, ArCH3), 2.11 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H). 13CNMR (100 MHz, CDCl3) δ=173.6, 170.4, 170.1, 170.0, 169.5, 161.2, 153.7,141.2, 117.2, 99.3, 72.4, 71.7, 71.2, 68.3, 61.5, 20.8, 20.6, 15.2.ESIMS(+): m/z 457.00 [M+H]+, 479.15 [M+Na]+.

2-Methyl-4H-pyran-4-one-3-β-D-glucopyranoside (4). The synthesis of 4was accomplished following the procedure for the synthesis of 2 using0.15 g (0.33 mmol) of 4a and 0.23 mL (0.99 mmol) of NaOMe (25% in MeOH)in 10 mL of dry MeOH. 4 was collected as a white solid in 95% yield(0.90 g, 0.31 mmol). 1H NMR (500 MHz, CD3OD) δ=7.99 (d, J=5.2 Hz, 1H),6.43 (d, J=5.7 Hz, 1H), 4.79 (d, J=7.5 Hz, 1H), 3.81 (dd, J1=12.0 Hz,J2=2.3 Hz, 1H, CHCHaHbOH), 3.65 (dd, J1=12.1H, J2=5.2 Hz, 1H,CHCHaHbOH), 3.39 (t, J=9.2 Hz, 1H), 3.36 (t, J=8.6 Hz, 1H), 3.32 (t,J=9.2 Hz, 1H), 3.23 (m, 1H, CHCHaHbOH), 2.45 (s, 3H, ArCH3). 13C NMR(125 MHz, CD3OD) δ=175.9, 163.3, 155.9, 142.3, 116.0, 104.1, 77.2, 76.7,74.1, 69.7, 61.2, 14.6. ESI-MS(+): m/z 288.85 [M+H]+, 311.03 [M+Na]+.HRMS calcd for C12H16O8Na: 311.0737. Found: 311.0742. Anal. calcd forC12H16O8Na.H2O: C, 43.77; H, 5.51. Found: C, 44.08; H, 5.58.

2-Methyl-4H-pyran-4-thione-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside)(6a). 4a (0.20 g, 0.43 mmol) was dissolved in 15 mL of benzene andheated to 80° C. To this was added P4S10 (0.07 g, 0.16 mmol) andhexamethyldisilyloxane (0.30 mL, 1.43 mmol). The reaction was heated toreflux for 45 min. After cooling to room temperature the reaction wasfiltered and concentrated for column purification in 1% MeOH in CH₂Cl₂yielding 6a as an orange solid in 83% yield (0.17 g, 0.36 mmol). 1H NMR(500 MHz, CDCl3) δ=7.40 (d, J=5.2 Hz, 1H), 7.15 (d, J=5.2 Hz, 1H), 5.52(d, J=8.1 Hz, 1H), 5.30 (t, J=9.8 Hz, 1H), 5.24 (t, J=7.5 Hz, 1H), 5.11(t, J=9.2 Hz, 1H), 4.18 (dd, J1=12.6 Hz, J2=4.6 Hz, 1H, CHCHaHbOAc),4.12 (dd, J1=12.6H, J2=2.9 Hz, 1H, CHCHaHbOAc), 3.61 (dq, J1=12.1 Hz,J2=2.3 Hz, 1H, CHCHaHbOAc), 2.33 (s, 3H, ArCH3), 2.14 (s, 3H), 2.03 (s,3H), 2.01 (s, 6H). 13C NMR (125 MHz, CDCl3) δ=193.4, 170.4, 170.1,170.0, 169.5, 158.3, 149.1, 145.7, 128.9, 98.4, 72.3, 71.7, 71.1, 68.4,61.4, 21.1, 20.6, 15.8. ESI-MS(+): m/z 472.63 [M+H]+, 494.94 [M+Na]+.

2-Methyl-4H-pyran-4-thione-3-β-D-glucopyranoside (6). The synthesis of 6was accomplished following the procedure for the synthesis of 2 using0.16 g (0.34 mmol) of 6a and 0.23 mL (1.0 mmol) of NaOMe (25% in MeOH)in 10 mL of dry MeOH. 6 was collected as an orange solid in 35% yield(0.035 g, >98% pure by HPLC analysis). 1H NMR (500 MHz, CD3OD) δ=7.76(d, J=5.2 Hz, 1H), 7.23 (d, J=5.2 Hz, 1H), 5.00 (d, J=8.1 Hz, 1H), 3.82(dd, J1=12.1 Hz, J2=2.3 Hz, 1H, CHCHaHbOH), 3.64 (dd, J1=12.1 Hz, J2=5.7Hz, 1H, CHCHaHbOH), 3.47 (t, J=8.1 Hz, 1H), 3.40 (t, J=9.2 Hz, 1H), 3.31(t, J=9.7 Hz, 1H), 3.21 (dq, J1=9.8 Hz, J2=2.3 Hz, 1H, CHCHaHbOH), 3.12(s, 3H, ArCH3). 13C NMR (125 MHz, CD3OD) δ=193.7, 159.3, 150.2, 147.3,127.8, 102.8, 77.0, 76.5, 74.4, 69.6, 67.6, 61.2, 15.2. ESI-MS(+): m/z304.78 [M+H]+, 326.96 [M+Na]+. HRMS calcd for C12H16O7SNa: 327.0509.Found: 327.0508. Anal. calcd for C12H16O7S. 0.5H₂O: C, 46.00; H, 5.47;S, 10.23. Found: C, 45.91; H, 5.79; S, 10.78.

N-(Biphenyl-4-ylmethyl)-1-hydroxy-6-oxo-1,6-dihydropyridine-2-carboxamide,1,2-HOPO-2 (7). This compound was prepared as previously reported(Agrawal, A.; Romero-Perez, D.; Jacobsen, J. A.; Villareal, F. J.;Cohen, S. M. ChemMedChem, 2008, 3, 812-820). 1H NMR (500 MHz, DMSO-d6)δ=9.32 (t, J=6.3 Hz, 1H, NH), 7.62 (m, 4H), 7.43 (m, 6H), 7.33 (t, J=7.5Hz, 1H), 6.57 (dd, J1=9.2 Hz, J2=1.7 Hz, 1H), 6.32 (dd, J1=8.6 Hz,J2=1.8 Hz, 1H), 4.45 (d, J=5.7 Hz, 2H, NCH2). APCI-MS(−): m/z 319.09[M−H]−. Anal. calcd for C19H16N2O₃: C, 71.24; H, 5.03; N, 8.74. Found:C, 71.27; H, 5.40; N, 8.84.

N-(Biphenyl-4-ylmethyl)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1,6-dihydropyridin-6(1H)-one-2-carboxamide(8a). In 10 mL of dry DMF was added 7 (0.10 g, 0.31 mmol), Cs2CO3 (0.30g, 0.94 mmol), and acetobromo-α-D-glucose (0.14 g, 0.34 mmol). Thereaction was left stirring at room temperature under N2 for 24 h.Following evaporation of the solvents, the crude product was brought upin EtOAc and washed once each with water and brine. The organic layerwas dried over MgSO₄, filtered, and concentrated for purification on asilica gel column eluting with 1% MeOH in EtOAc to yield 8a as a whitesolid in 80% yield (0.16 g, 0.25 mmol). 1H NMR (500 MHz, CDCl3) δ=7.75(d, J=8.5 Hz, 2H), 7.66 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.40(t, J=7.5 Hz, 2H), 7.35 (t, J=5.8 Hz, 1H), 7.30 (t, J=6.3 Hz, 1H), 6.67(dd, J1=9.2 Hz, J2=1.7 Hz, 1H), 6.56 (dd, J1=6.9 Hz, J2=1.8 Hz, 1H),5.52 (d, J=8.6 Hz, 1H), 5.14 (t, J=9.5 Hz, 1H), 4.73 (dd, J1=14.4 Hz,J2=6.3 Hz, 1H, NHCHaHbAr), 4.68 (t, J=8.0 Hz, 1H), 4.57 (t, J=10.3 Hz,1H), 4.55 (dd, J1=8.6 Hz, J2=2.9 Hz, 1H, NHCHaHbAr), 4.31 (dd, J1=12.6Hz, J2=6.3 Hz, 1H, CHCHaHbOAc), 3.76 (dd, J1=12.6 Hz, J2=2.3 Hz, 1H,CHCHaHbOAc), 3.56 (dq, J1=8.1 Hz, J2=2.3 Hz, 1H, CHCHaHbOAc), 2.09 (s,3H), 1.98 (s, 3H), 1.94 (s, 3H), 1.62 (s, 3H). 13C NMR (125 MHz, CDCl3)δ=170.9, 169.9, 169.8, 169.4, 159.3, 157.7, 143.3, 140.8, 140.7, 138.7,136.8, 129.1, 128.8, 127.9, 127.4, 127.2, 124.1, 106.9, 101.1, 72.9,71.6, 69.5, 68.2, 61.4, 43.8, 20.8, 20.6, 20.0. ESI-MS(+): m/z 650.92[M+H]+, 673.22 [M+Na]+.

N-(Biphenyl-4-ylmethyl)-6-oxo-1-(β-D-glucopyranosyloxy)-1,6-dihydropyridine-2-carboxamide(8). 8a (0.086 g, 0.13 mmol) was dissolved in dry MeOH (3 mL) in an icebath. After stirring at 0° C. for 10 min, 30 μL (0.13 mmol) of NaOMe(25% in MeOH) was added. The reaction was stopped after 1 h by theaddition of a ˜100 mg of cation exchange resin (Biorad AG-50W-X8, H+form) which was allowed to stir for an additional 10 minutes. The crudeproduct was filtered, concentrated, and purified via silica gelchromatography eluting with 0-1% MeOH in CH2Cl2 yielding a white solidin 79% yield (0.05 g, >93% pure by HPLC analysis). 1H NMR (500 MHz,CD3OD) δ=7.62 (m, 4H), 7.54 (t, J=6.9 Hz, 1H), 7.47 (d, J=8.0 Hz, 2H),7.40 (t, J=8.0 Hz, 2H), 7.30 (t, J=7.5 Hz, 1H), 6.73 (dd, J1=9.2 Hz,J2=1.7 Hz, 1H), 6.51 (dd, J1=6.9 Hz, J2=1.7 Hz, 1H), 5.01 (d, J=8.0 Hz,1H), 4.62 (d, J=14.9 Hz, 1H, NHCHaHbAr), 4.45 (d, J=14.9 Hz, 1H,NHCHaHbAr), 3.64 (dd, J1=12.0 Hz, 2.9 Hz, 1H, CHCHaHbOH), 3.37 (m, 2H),3.28 (t, J=8.6 Hz, 1H), 3.17 (dq, J1=6.3 Hz, J2=2.3 Hz, 1H, CHCHaHbOH),3.12 (t, J=9.8 Hz, 1H). 13C NMR (125 MHz, CD3OD) δ=161.9, 158.9, 144.6,140.7, 140.5, 139.7, 136.8, 128.5, 126.9, 126.7, 122.7, 106.6, 105.8,77.1, 76.3, 72.3, 69.8, 61.1, 47.2. ESIMS(+): m/z 504.97 [M+Na]+. HRMScalcd for C25H26N2O8Na: 505.1581. Found: 505.1576. Anal. calcd forC25H26N2O8.0.5Na.2CH₃OH: C, 58.11; H, 6.14; N, 5.02. Found: C, 57.74; H,6.31; N, 5.10.

Example 2 Exemplary Syntheses Related to Sulfonate Ester ZBGs s

General Procedure for the Synthesis of Sulfonate Ester ZBGs. The ZBGcompound was dissolved in pyridine on ice. To this was added the desiredsulfonyl chloride. The reaction flask was removed from the ice bath andleft stirring overnight under nitrogen while warming to roomtemperature. The pyridine was removed by rotary evaporation and theresulting oil was re-dissolved in dichloromethane and washed with 1 MHCl (˜30 mL), water, and brine. The organic layer was dried over MgSO₄,filtered, and then concentrated via rotary evaporation. The product waspurified on a silica gel column eluting with 1% MeOH in CH₂Cl₂ unlessotherwise noted.

2-Oxopyridin-1(2H)-yl benzenesulfonate(PZBG-1a).2-Hydroxypyridine-1-oxide (1.0 g, 9.1 mmol) was reacted withbenzenesulfonyl chloride (1.27 mL, 10.0 mmol) in 75 mL of pyridine toafford PZBG-1a in 77% yield (1.75 g, 7.0 mmol). ¹H NMR (500 MHz, CDCl₃)δ=8.02 (d, J=8.0 Hz, 2H), 7.75 (t, J=8.0 Hz, 1H), 7.59 (m, 3H), 7.28(dt, J₁=6.9 Hz, J₂=2.3 Hz, 1H), 6.52 (d, J=9.8 Hz, 1H), 6.15 (t, J=7.5Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ=157.0, 139.7, 137.1, 136.0, 133.8,130.0, 129.5, 123.4, 105.4. ESI-MS(+): m/z 252.01 [M+H]+, 273.95[M+Na]⁺. Anal. calcd for C₁₁H₉NO₄S: C, 52.58; H, 3.61; N, 5.57. Found:C, 52.21; H, 3.99; N, 5.44.

2-Oxopyridin-1(2H)-yl-4-methylbenzenesulfonate (PZBG-1b).2-Hydroxypyridine-1-oxide (0.5 g, 4.5 mmol) was reacted withp-toluenesulfonyl chloride (2.57 g, 13.5 mmol) in 40 mL of pyridine toafford PZBG-1b in 89% yield (1.06 g, 4.0 mmol). ¹H NMR (500 MHz,DMSO-d₆) δ=7.82 (d, J=8.6 Hz, 2H), 7.75 (dd, J₁=7.5 Hz, J₂=1.8 Hz, 1H),7.49 (d, J=8 Hz, 2H), 7.41 (dt, J₁=7.5 Hz, J₂=1.7 Hz, 1H), 6.48 (dd,J₁=9.2 Hz, J₂=1.8 Hz, 1H), 6.21 (dt, J₁=7.5 Hz, J₂=1.8 Hz, 1H), 2.42 (s,3H, CH₃). ¹³C NMR (100 MHz, CDCl₃) δ=156.6, 148.9, 141.2, 138.1, 131.1,130.5, 130.0, 122.9, 106.1, 22.0. ESI-MS(+): m/z 266.10, [M+H]⁺, 287.99[M+Na]⁺. Anal. calcd for C₁₂H₁₁NO₄S: C, 54.33; H, 4.18; N, 5.28. Found:C, 54.24; H, 4.35; N, 5.24.

2-Oxopyridin-1(2H)-yl 4-nitrobenzenesulfonate (PZBG-1c).2-Hydroxypyridine-1-oxide (0.5 g, 4.5 mmol) was reacted with4-nitrobenzenesulfonyl chloride (3.0 g, 13.5 mmol) in 40 mL of pyridineto afford PZBG-1c in 92% yield (1.23 g, 4.2 mmol). ¹H NMR (500 MHz,CDCl₃) δ=8.42 (d, J=8.6 Hz, 2H), 8.23 (d, J=9.2 Hz, 2H), 7.65 (dd,J₁=7.5 Hz, J₂=1.8 Hz, 1H), 7.34 (dt, J₁=9.2 Hz, J₂=1.7 Hz, 1H), 6.52 (d,J=9.2 Hz, 1H), 6.22 (t, J=7.7 Hz, 1H). ¹³C NMR (100 MHz, DMSO) δ=156.6,152.3, 141.6, 139.4, 138.3, 131.8, 125.6, 122.8, 106.4. ESI-MS(+): m/z297.28 [M+H]⁺, 319.02 [M+Na]⁺.

2-Oxopyridin-1(2H)-yl 2,4-dinitrobenzenesulfonate (PZBG-1d).2-Hydroxypyridine-1-oxide (0.5 g, 4.5 mmol) was reacted with2,4-dinitrobenzenesulfonyl chloride (1.32 g, 5.0 mmol) in 40 mL ofpyridine to afford PZBG-1d in 31% yield (0.48 g, 1.4 mmol). ¹H NMR (500MHz, CDCl₃) δ=8.96 (d, J=2.3 Hz, 1H), 8.42 (dd, J₁=9.2 Hz, J₂=2.3 Hz,1H), 7.68 (dd, J₁=6.9 Hz, J₂=1.7 Hz, 1H), 7.50 (dt, J₁=7.5 Hz, J₂=2.3Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.82 (dd, J₁=9.2 Hz, J₂=1.8 Hz, 1H),6.35 (dt, J₁=6.9 Hz, J₂=1.8 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ=157.0,155.6, 140.5, 135.1, 129.6, 124.0, 122.9, 116.0, 106.6.

4-(((2-Oxopyridin-1(2H)-yl)oxy)sulfonyl)benzoic acid (PZBG-1e).2-Hydroxypyridine-1-oxide (0.21 g, 1.9 mmol) was reacted with4-(chlorosulfonyl)benzoic acid (0.62 g, 2.8 mmol) in 5 mL pyridine. Thesolvent was evaporated, leaving a yellow oil. Addition of 5 mL ofdichloromethane followed by the addition of 5 mL of ethyl acetateallowed for precipitation of PZBG-1e in 30% yield (0.17 g, 0.57 mmol).¹H NMR (400 MHz, DMSO) δ=8.18 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.4 Hz),7.88 (dd, J₁=7.6 Hz, J₂=2 Hz), 7.45 (td, J₁=8.2 Hz, J₂=2 Hz, 1H), 6.50(dd, J₁=9.2 Hz, J₂=1.6 Hz, 1H), 6.26 (td, J₁=7 Hz, J₂=1.6 Hz, 1H). ¹³CNMR (100 MHz, CDCl₃) δ=166.5, 156.6, 141.5, 138.2, 137.9, 137.3, 131.2,130.4, 122.8, 106.2. ESI-MS(−): m/z 294.26[M−H]⁻. Anal. calcd. forC₁₂H₉NO₆S: C, 48.81; H, 3.07; N, 4.74. Found: C, 48.91; H, 3.37; N,4.84.

2-Methyl-4-oxo-4H-pyran-3-yl benzenesulfonate (PZBG-2a).3-Hydroxy-2-methyl-4H-pyran-4-one (1.0 g, 7.9 mmol) was reacted withbenzenesulfonyl chloride (3.0 mL, 23.7 mmol) in 75 mL of pyridine toafford PZBG-2a in 71% yield (1.50 g, 5.6 mmol). ¹H NMR (500 MHz, CDCl₃)δ=8.12 (d, J=8.6 Hz, 2H), 7.69 (t, J=7.5 Hz, 1H), 7.65 (d, J=5.8 Hz,1H), 7.58 (t, J=8.0 Hz, 2H), 6.33 (d, J=5.2 Hz, 1H), 2.46 (s, 3H, CH₃).¹³C NMR (100 MHz, CDCl3) δ=172.1, 163.1, 154.3, 138.4, 136.6, 134.7,129.2, 129.0, 117.7, 16.3. ESI-MS(+): m/z 267.06 [M+H]⁺, 289.03 [M+Na]⁺.

2-Methyl-4-oxo-4H-pyran-3-yl 4-methylbenzenesulfonate (PZBG-2b).3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted withp-toluenesulfonyl chloride (2.27 g, 11.9 mmol) in 40 mL of pyridine toafford PZBG-2b in 64% yield (0.71 g, 2.5 mmol). ¹H NMR (500 MHz, CDCl₃)δ=7.99 (d, J=8 Hz, 2H), 7.64 (d, J=5.8 Hz, 1H), 7.37 (d, J=8 Hz, 2H),6.34 (d, J=5.8 Hz, 1H), 2.46 (s, 3H, CH₃), 2.45 (s, 3H, CH₃). ¹³C NMR(100 MHz, CDCl₃) δ=127.2, 163.2, 154.2, 145.8, 138.4, 133.6, 129.8,129.0, 117.7, 22.0, 16.3. ESI-MS(+): m/z 281.01 [M+H]⁺, 303.03 [M+Na]⁺.

2-Methyl-4-oxo-4H-pyran-3-yl 4-nitrobenzenesulfonate (PZBG-2c).3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted with4-nitrobenzenesulfonyl chloride (0.88 g, 4.0 mmol) in 15 mL of pyridineto afford PZBG-2c in 58% yield (0.71 g, 2.3 mmol). ¹H NMR (500 MHz,CDCl₃) δ=8.42 (d, J=9.2 Hz, 2H), 8.31 (d, J=9.2 Hz, 2H), 7.69 (d, J=5.7Hz, 1H), 6.34 (d, J=5.8 Hz, 1H), 2.53 (s, 3H, CH₃). ¹³C NMR (100 MHz,CDCl₃) δ=171.8, 163.5, 154.6, 151.2, 142.3, 138.6, 130.4, 124.3, 117.6,16.3. ESI-MS(+): m/z 312.06 [M+H]⁺.

2-Methyl-4-oxo-4H-pyran-3-yl 2,4-dinitrobenzenesulfonate (PZBG-2d).3-Hydroxy-2-methyl-4H-pyran-4-one (0.5 g, 4.0 mmol) was reacted with2,4-dinitrobenzenesulfonyl chloride (1.58 g, 5.9 mmol) in 40 mL ofpyridine to afford PZBG-2d in 28% yield (0.39 g, 1.1 mmol). ¹H NMR (500MHz, CDCl₃) δ=8.72 (d, J=2.3 Hz, 1H), 8.56 (dd, J₁=9.2 Hz, J₂=2.3 Hz,1H), 8.44 (d, J=8.6 Hz, 1H), 7.71 (d, J=5.8 Hz, 1H), 6.31 (d, J=5.8 Hz,1H), 2.53 (s, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃) δ=171.6, 163.3, 154.9,139.3, 136.4, 133.8, 126.8, 120.5, 117.5, 16.1. ESI-MS(+): m/z 357.03[M+H]⁺, 378.99 [M+Na]⁺.

1,2-Dimethyl-4-oxo-1,4-dihydropyridin-3-yl benzenesulfonate (PZBG-3a).3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.5 g, 3.6 mmol) was reactedwith benzenesulfonyl chloride (0.51 mL, 4.0 mmol) in 40 mL of pyridineto afford PZBG-3a in 43% yield (0.43 g, 1.5 mmol). ¹H NMR (500 MHz,CDCl₃) δ=8.19 (d, J=6.9 Hz, 2H), 7.66 (t, J=7.5 Hz, 1H), 7.57 (t, J=7.5Hz, 2H), 7.23 (d, J=8 Hz, 1H), 6.34 (d, J=8.1 Hz, 1H), 3.63 (s, 3H,NCH₃), 2.49 (s, 3H, CH₃). ¹³C NMR (100 MHz, CDCl₃) δ=171.3, 144.8,140.7, 139.9, 137.3, 134.3, 129.0, 128.9, 118.3, 41.8, 14.7. ESI-MS(+):m/z 280.09 [M+H]⁺.

1,2-Dimethyl-4-oxo-1,4-dihydropyridin-3-yl 4-methylbenzenesulfonate(PZBG-3b). 3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.2 g, 1.4 mmol) wasreacted with p-toluenesulfonyl chloride (0.82 g, 4.3 mmol) in 10 mL ofpyridine to afford PZBG-3b in 86% yield (0.35 g, 1.2 mmol). ¹H NMR (500MHz, CDCl₃) δ=7.99 (d, J=8.4 Hz, 2H), 7.40 (d, J=7.6 Hz, 1H), 7.33 (d,J=8 Hz, 2H), 6.40 (d, J=7.2 Hz, 1H), 3.64 (s, 3H), 2.42 (s, 3H), 2.41(s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ=170.71, 145.67, 145.54, 141.48,134.07, 129.72, 128.96, 126.07, 117.53, 42.25, 22.00, 14.7. ESI-MS(+):m/z 294.05 [M+H]⁺, 315.97 [M+Na]⁺.

1,2-Dimethyl-4-oxo-1,4-dihydropyridin-3-yl 4-nitrobenzenesulfonate(PZBG-3c). 3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.2 g, 1.5 mmol) wasreacted with 4-nitrobenzenesulfonyl chloride (0.488 g, 2.2 mmol) in 10mL of pyridine to afford PZBG-3c in 50% yield (0.23 g, 0.7 mmol). ¹H NMR(400 MHz, CDCl₃) δ=8.41-8.34 (m, 4H), 7.26 (d, J=7.6 Hz, 1H), 6.33 (d,J=7.6 Hz, 1H), 3.67 (s, 3H), 2.53 (s, 3H). ¹³C NMR (100 MHz, CDCl₃)6=170.9, 150.9, 144.9, 143.2, 140.9, 140.1, 130.4, 124.0, 118.4, 41.9,14.6. ESI-MS(+): m/z 325.11 [M+H]⁺, 346.96 [M+Na]⁺.

1,2-Dimethyl-4-oxo-1,4-dihydropyridin-3-yl 2,4-dinitrobenzenesulfonate(PZBG-3d). 3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (0.10 g, 0.73 mmol)was reacted with 2,4-dinitrobenzenesulfonyl chloride (0.3 g, 1.1 mmol)in 10 mL of pyridine to afford PZBG-3d in 23% yield (0.07 g, 0.2 mmol).¹H NMR (400 MHz, CDCl₃) δ=8.83 (d, J=2.8 Hz 1H), 8.37 (dd, J₁=9.6 Hz,J₂=2.8 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 6.25 (d,J=7.6 Hz, 1H), 3.68 (s, 3H), 2.31 (s, 3H). ¹³C NMR (100 MHz, CDCl₃)δ=169.35, 154.98, 144.00, 142.61, 141.42, 140.76, 138.54, 129.69,122.24, 118.15, 116.78, 59.63, 13.29.

7-Oxocyclohepta-1,3,5-trien-1-yl benzenesulfonate (PZBG-4a).2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted withbenzenesulfonyl chloride (0.63 mL, 4.9 mmol) in 5 mL of pyridine toafford PZBG-4a in 76% yield (0.33 g, 1.3 mmol). ¹H NMR (400 MHz, DMSO)δ=7.95 (d, J=7.6 Hz, 2H), 7.80 (t, J=7.6 Hz, 1H), 7.67 (t, J=8 Hz, 2H),7.43-7.37 (m, 2H), 7.25 (t, J=8.4 Hz, 1H), 7.14-7.09 (m, 2H). ¹³C NMR(100 MHz, CDCl₃) δ=179.24, 154.79, 141.19, 138.21, 136.37, 136.33,135.57, 131.96, 130.92, 130.27, 128.76. ESI-MS(+): m/z 262.97 [M+H]⁺,279.72 [M+NH₄]⁺, 284.99 [M+Na]⁺.

7-Oxocyclohepta-1,3,5-trien-1-yl 4-methylbenzenesulfonate (PZBG-4b).2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted withp-toluenesulfonyl chloride (0.41 g, 2.0 mmol) in 10 mL of pyridine toafford PZBG-4b in 63% Yield (0.04 g, 0.1 mmol). ¹H NMR (400 MHz, CDCl₃)δ=7.92 (d, J=8.4 Hz, 2H), 7.46 (d, J=9.2 Hz, 1H), 7.35 (d, J=8.4 Hz,2H), 7.26-7.16 (m, 2H), 7.13-7.06 (m, 1H), 6.98 (t, J=10 Hz, 1H), 2.45(s, 3H). ¹³C (125 MHz, CDCl₃) δ=179.41, 155.15, 145.50, 141.23, 136.32,134.61, 133.41, 130.81, 130.00, 129.60, 128.59, 21.78. ESI-MS(+): m/z277.21 [M+H]⁺, 293.99 [M+NH₄]⁺.

7-Oxocyclohepta-1,3,5-trien-1-yl 4-nitrobenzenesulfonate (PZBG-4c).2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with4-nitrobenzenesulfonyl chloride (1.1 g, 4.9 mmol) in 5 mL of pyridine.Addition of 10 mL of water allowed for precipitation of PZBG-4c in 71%yield (0.38 g, 1.2 mmol) without the need for further purification. ¹HNMR (400 MHz, DMSO) δ=8.45 (d, J=8.8 Hz, 2H), 8.22 (d, J=8.8 Hz, 2H),7.52 (d, J=9.2 Hz, 1H), 7.46 (dd, J₁=10.2 Hz, J₂=3.6 Hz, 1H), 7.31 (dd,J₁=9.8 Hz, J₂=2 Hz, 1H), 7.15 (dd, J₁=10.6 Hz, J₂=3.6 Hz, 1H). ¹³C (100MHz, CDCl₃) δ=179.09, 154.86, 151.50, 141.95, 141.27, 138.59, 136.87,132.06, 131.48, 130.42, 125.42. ESI-MS(+): m/z 308.01 [M+H]⁺, 324.73[M+NH₄]⁺

7-Oxocyclohepta-1,3,5-trien-1-yl 2,4-dinitrobenzenesulfonate (PZBG-4d).2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with2,4-dinitrobenzenesulfonyl chloride (0.54 g, 2.0 mmol) in 10 mL ofpyridine to afford PZBG-4d in 6% Yield (0.04 g, 0.1 mmol). ¹H NMR (400MHz, DMSO) δ=9.00 (d, J=2.4 Hz 1H), 8.66 (dd, J₁=8.8 Hz, J₂=2.4 Hz, 1H),8.38 (d, J=8.8 Hz 1H), 7.66 (d, J=9.6 Hz 1H), 7.50 (td, J₁=8.4 Hz,J₂=3.6 Hz, J₃=1.2 Hz, 1H), 7.35 (td, J₁=8.4 Hz, J₂=2.4 Hz, 1H),7.20-7.15 (m, 2H). ¹³C (125 MHz, DMSO) δ=178.71, 155.30, 151.20, 147.90,140.96, 138.83, 137.10, 134.58, 133.22, 131.93, 131.55, 127.92, 121.11.ESI-MS(+): m/z 353.15 [M+H]⁺, 375.11 [M+Na]⁺.

6-(([1,1′-Biphenyl]-4-ylmethyl)carbamoyl)-2-Oxopyridin-1(2H)-ylbenzenesulfonate (1a). 1,2-HOPO-2 was prepared as previously reported[38]. In a 10 mL round bottom flask was dissolved 0.05 g (0.16 mmol) of1,2-HOPO-2 in 3 mL of pyridine. To this was added 60 μL (0.5 mmol) ofbenzenesulfonyl chloride. The reaction was left stirring under N₂ atroom temperature overnight. After 16 h, the solvent was evaporated toleave an orange oil which was dissolved in CH₂Cl₂ and washed once with 1M HCl then brine. The organic layer was dried over MgSO₄, filtered andconcentrated. Product was purified on a silica gel column eluting with1% MeOH with CH₂Cl₂ to afford 1a in 67% yield (0.05 g, 0.1 mmol). ¹H NMR(400 MHz, CDCl₃) δ=8.01 (d, J=7.6 Hz, 2H), 7.76 (t, J=7.6 Hz, 1H), 7.61(m, 6H), 7.47 (m, 4H), 7.38-7.31 (m, 2H), 6.62 (d, J=8.0 Hz, 1H), 6.57(d, J=6.4 Hz, 1H), 4.63 (d, J=5.2 Hz, 2H). ¹³C (100 MHz, CDCl₃) δ=159.2,157.0, 142.7, 141.2, 140.8, 138.9, 136.0, 134.5, 129.9, 129.5, 129.1,128.9, 127.8, 127.7, 127.3, 125.2, 107.6, 44.5. ESI-MS(+): m/z 461.13[M+H]⁺, 483.13 [M+Na]⁺. Anal. calcd for C₂₅H₂₀N₂O₅S.0.5H₂O: C, 63.95; H,4.51; N, 5.99. Found: C, 63.68; H, 5.14; N, 5.99.

4-(((6-(([1,1′-Biphenyl]-4-ylmethyl)carbamoyl)-2-Oxopyridin-1(2H)yl)oxy)sulfonyl)benzoic acid (1b). 1,2-HOPO-2 (0.20 g, 0.6 mmol) wasdissolved in 5 mL of pyridine. To this was added4-(chlorosulfonyl)benzoic acid (0.21 g, 1.0 mmol). The reaction wasallowed to proceed overnight at room temperature. The solvent wasevaporated and to the remaining oil was added 5 mL of dichloromethanefollowed by 5 mL of ethyl acetate, allowing for precipitation. The solidwhite product was filtered and collected in 14% yield (0.04 g, 0.08mmol). ¹H NMR (400 MHz, DMSO) δ=9.36 (t, J=5.6 Hz, 1H, NH), 8.18 (d,J=8.8 Hz, 2H), 8.06 (d, J=8.8 Hz, 2H), 7.66-7.61 (m, 4H), 7.53 (dd,J₁=7.8 Hz, J₂=2.8 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.38-7.33 (m, 3H),6.67 (dd, J₁=9.2 Hz, J₂=1.6 Hz, 1H), 6.47 (dd, J₁=6.4 Hz, J₂=1.2 Hz,1H), 4.27 (d, J=5.6 Hz, 2H). ¹³C NMR (100 MHz, DMSO) δ=166.55, 159.45,156.86, 143.21, 140.61, 140.54, 139.68, 138.26, 138.02, 137.61, 130.97,130.09, 129.62, 128.73, 128.08, 127.33, 127.28, 124.19, 107.11, 43.05.ESI-MS(−): m/z 502.89 [M−H]⁺. Anal. calcd for C₂₆H₂₀N₂O₇S. 0.25HCl: C,60.80; H, 3.97; N, 5.45. Found: C, 60.92; H, 4.30; N, 5.73.

2-(([1,1′-Biphenyl]-4-ylmethyl)carbamoyl)-4-oxo-4H-pyran-3-ylbenzenesulfonate (2a). PY-2 was prepared as previously reported [38]. Ina 50 mL round bottom flask was dissolved 0.20 g (0.6 mmol) of PY-2 in 15mL of pyridine. To this was added 240 μL (1.8 mmol) of benzenesulfonylchloride. The reaction was left stirring under N₂ at room temperatureovernight. After 16 h, the solvent was evaporated to leave a red oilwhich was dissolved in CH₂Cl₂ and washed once with 1 M HCl then brine.The organic layer was dried over MgSO₄, filtered and concentrated.Product was precipitated from MeOH to afford 2a in 12% yield (0.03 g,0.07 mmol). ¹H NMR (400 MHz, CDCl₃) δ=8.10 (d, J=8.4 Hz, 2H), 7.80 (d,J=5.6 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.61 (m, 6H), 7.47-7.36 (m, 6H),6.47 (d, J=6.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃)δ=172.7, 157.3, 154.8, 151.3, 141.2, 140.8, 139.2, 136.0, 135.8, 135.2,129.3, 129.2, 129.1, 128.9, 127.8, 127.7, 127.3, 118.4, 44.3. ESI-MS(+):m/z 461.98 [M+H]⁺, 484.02 [M+Na]⁺.

Example 3 Exemplary Syntheses Related to Boronic Ester Compounds

The preparation of ZBGs with boronic ester protecting groups that can beselectively cleaved in the presence of H₂O₂ has been conducted. Arepresentative synthesis of a ZBG with a boronic ester protecting groupis shown in FIG. 18 (Top).

Methyl2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzoate(B1). To 5 ml, of acetonitrile was added methyl 2-hydroxybenzoate (85μL, 0.66 mmol), K₂CO₃ (273 mg, 2.0 mmol), and 4-bromomethylphenylboronic acid pinacol ester (217 mg, 0.73 mmol). The reaction was heatedto 70° C. under nitrogen overnight. After removal of the solvent viarotary evaporation, the resulting oil was brought up in EtOAc and washedwith a saturated sodium bicarbonate solution to remove startingmaterials. The organic layer was dried over MgSO₄, filtered andconcentrated. The product was purified on a silica gel column elutingwith 5% EtOAc in hexanes to yield B1 as a white solid in 77% yield (186mg, 0.5 mmol). ¹H NMR (400 MHz, CDCl₃) δ=7.85-7.81 (m, 3H), 7.49 (d,J=7.6 Hz, 2H), 7.40 (dt, J₁=8.4 Hz, J₂=1.8 Hz, 1H), 7.00-6.96 (m, 2H),5.20 (s, 2H), 3.90 (s, 3H), 1.35 (s, 12H). ¹³C NMR (100 MHz, CDCl₃)δ=140.2, 135.2, 133.6, 132.0, 126.2, 121.0, 120.8, 114.0, 84.0, 70.7,52.3, 25.1. ESI-MS(+): m/z 368.82 [M+H]⁺, 385.69 [M+NH₄]⁺.

4-Nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbonate (B2a). 4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.5g, 2.1 mmol) was dissolved in 20 mL of dry THF. Triethylamine (0.6 mL,4.3 mmol) was added followed by 4-nitrophenyl chloroformate (0.47 g, 2.3mmol) and the reaction was allowed to stir at room temperature for 1 h.The reaction was diluted with EtOAc and washed with 1.0 M HCl followedby saturated NaHCO₃. The organic layer was dried over MgSO₄, filteredand concentrated. Compound B2a was purified on a silica gel columneluting with 5% EtOAc in hexanes to give 0.51 g (1.3 mmol, 60% yield) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.25 (d, J=9.2 Hz, 2H), 7.85(d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 5.31(s, 2H), 1.35 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=155.7, 152.7, 145.6,137.2, 135.4, 127.9, 125.5, 122.0, 84.2, 71.0, 25.1. ESI-MS(+): m/z417.19 [M+NH₄]⁺, 422.20 [M+Na]⁺.

Methyl2-((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)oxy)benzoate(B2). In 5 mL of anhydrous DMF was dissolved methyl 2-hydroxybenzoate(42 μL, 0.32 mmol), B2a (100 mg, 0.25 mmol), and K₂CO₃ (104 mg, 0.75mmol). The reaction was allowed to stir at 80° C. for 1.5 h. The solventwas removed by rotary evaporation and the residue was redissolved inEtOAc and washed three times with water and once with brine. The organiclayer was dried over MgSO₄, filtered, and concentrated. Product was ranon a silica gel column and eluted with 10% EtOAc in hexanes yielding B2in 34% yield (35 mg, 0.085 mmol). ¹H NMR (400 MHz, CDCl₃) δ=8.02 (dd,J₁=7.8 Hz, J₂=1.7 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.56 (td, J₁=7.7 Hz,J₂=1.4 Hz, 1H), 7.45 (d, J=7.6 Hz, 2H), 7.34 (td, J₁=7.7 Hz, J₂=1.2 Hz,1H), 7.19 (dd, J₁=8.1 Hz, J₂=1.2 Hz, 1H), 5.32 (s, 2H), 3.76 (s, 3H),1.35 (s, 12H). ¹³C (100 MHz, CDCl₃)=153.6, 150.9, 138.0, 135.3, 134.2,132.2, 127.8, 126.7, 125.5, 123.6, 123.4, 122.0, 84.2, 70.6, 52.5, 25.1.ESI-MS(+): m/z 429.94 [M+NH₄]⁺, 434.94 [M+Na]⁺.

Methyl 2-(((trifluoromethyl)sulfonyl)oxy)benzoate (B3a). In 10 mL ofanhydrous DMF was dissolved methyl 2-hydroxybenzoate (170 μL, 1.3 mmol),N-phenyl bis(trifluoromethanesulfonate) (0.56 g, 1.5 mmol), and DIPEA(680 μL, 3.9 mmol). The reaction was allowed to stir at room temperatureovernight. The solvent was removed by rotary evaporation and the residuewas redissolved in EtOAc and washed three times with water and once withbrine. The organic layer was dried over MgSO₄, filtered, andconcentrated. Product was ran on a silica gel column and eluted with 10%EtOAc in hexanes yielding B3a in quantitative yield (0.36 g, 1.3 mmol).¹H NMR (400 MHz, CDCl₃) δ=8.03 (dd, J₁=7.8 Hz, J₂=1.7 Hz, 1H), 7.58 (td,J₁=8.2 Hz, J₂=1.7 Hz, 1H), 7.42 (td, J₁=7.6 Hz, J₂=1.1 Hz, 1H), 7.28(dd, J₁=7.8 Hz, J₂=2.0 Hz, 1H), 3.91 (s, 3H). ¹³C NMR (100 MHz, CDCl₃)δ=164.6, 148.5, 134.6, 132.3, 129.8, 128.7, 124.5, 117.3, 52.9.APCI-MS(+): m/z 284.88 [M+H]⁺.

Methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (B3). In5 mL of anhydrous DMF was added B3a (150 mg, 0.5 mmol), PdCl₂dppf.CH₂Cl₂(40 mg, 0.05 mmol), bis(pinacolato)diboron (190 mg, 0.75 mmol) and KOAc(147 mg, 1.5 mmol). The reaction was allowed to stir at 80° C. for 16 h.Upon cooling to room temperature, the reaction was filtered twicethrough celite and the resulting filtrate was concentrated and purifiedon a silica gel column eluting with 5% EtOAc in hexanes yielding B3 in18% yield (24 mg, 0.09 mmol). ¹H NMR (400 MHz, CDCl₃) δ=7.93 (d, J=7.7Hz, 1H), 7.50 (m, 2H), 7.40 (m, 1H), 3.91 (s, 3H), 1.42 (s, 12H). ¹³CNMR (100 MHz, CDCl₃) δ=133.8, 133.0, 132.5, 129.2, 128.9, 128.5, 84.4,74.3, 25.6. ESI-MS(+): m/z 262.88 [M+H]⁺.

Methyl2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thio)benzoate(B4). The synthesis of B4 was accomplished following the procedureoutlined for B1 using methyl 2-mercaptobenzoate (0.32 g, 1.9 mmol),4-bromomethylphenyl boronic acid pinacol ester (0.62 g, 2.1 mmol), and780 mg of K₂CO₃ (5.7 mmol) in 8 mL of anhydrous DMF. B4 was collected asa white solid in 40% yield (0.29 g, 0.76 mmol). ¹H NMR (400 MHz, CDCl₃)δ=7.95 (dd, J₁=7.9 Hz, J₂=1.4 Hz, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.43 (d,J=8.1 Hz, 2H), 7.38 (td, J₁=7.2 Hz, J₂=1.6 Hz, 1H), 7.30 (dd, J₁=8.0 Hz,J₂=0.8 Hz, 1H), 7.15 (td, J₁=7.8 Hz, J₂=1.2 Hz, 1H), 4.17 (s, 2H), 3.90(s, 3H), 1.34 (s, 12H). ¹³C (100 MHz, CDCl₃)=141.9, 139.7, 135.2, 132.6,131.5, 128.6, 127.8, 126.3, 124.3, 84.0, 52.3, 37.6, 25.1. ESI-MS(+):m/z 384.87 [M+H]⁺, 401.71 [M+NH₄]⁺.

Methyl2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)benzoate(B5). The synthesis of B5 was accomplished following the procedureoutlined for B1 using methyl 2-aminobenzoate (86 μL, 0.6 mmol),4-bromomethylphenyl boronic acid pinacol ester (0.22 g, 0.73 mmol), andK₂CO₃ (274 mg, 1.98 mmol) 5 mL of anhydrous DMF. B5 was collected in 33%(82 mg, 0.22 mmol) yield as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=8.20 (t, J=5.3 Hz, 1H, NH), 7.91 (dd, J₁=7.8 Hz, J₂=1.8 Hz, 1H), 7.78(d, J=8.1 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.26 (dt, J₁=7.2 Hz, J₂=1.6Hz, 1H), 6.58 (m, 2H), 4.47 (d, J=5.8 Hz, 2H), 3.87 (s, 3H), 1.34 (s,12H). ¹³C NMR (100 MHz, CDCl₃) δ=169.3, 151.3, 142.5, 135.4, 134.8,131.8, 126.6, 115.1, 112.0, 110.5, 83.9, 51.7, 47.3, 25.1. ESI-MS(+):m/z 367.98 [M+H]⁺.

Methyl4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)benzoate(B6). The synthesis of B6 was accomplished following the procedureoutlined for B1 using methyl 4-aminobenzoate (75 mg, 0.5 mmol),4-bromomethylphenyl boronic acid pinacol ester (0.15 g, 0.5 mmol), andK₂CO₃ (206 mg, 1.5 mmol) in 5 mL of anhydrous DMF.B6 was collected in20% (38 mg, 0.1 mmol) yield as a pale yellow solid. ¹H NMR (400 MHz,CDCl₃) δ=7.85 (d, J=7.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 6.57 (d, J=8.8 Hz, 2H), 4.40 (s, 2H), 3.84 (s, 3H), 1.34 (s,12H). ¹³C NMR (125 MHz, CDCl₃) δ=167.3, 151.7, 141.8, 135.4, 135.3,131.6, 126.7, 118.8, 111.7, 83.9, 51.6, 47.8, 24.9. ESI-MS(+): m/z368.02 [M+H]⁺.

Methyl4-(((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)methyl)benzoate(B7). The synthesis of B7 was accomplished following the procedureoutlined for B1 using methyl 4-(aminomethyl)benzoate hydrochloride (100mg, 0.5 mmol), 4-bromomethylphenyl boronic acid pinacol ester (0.15 g,0.5 mmol), and K₂CO₃ (207 mg, 1.5 mmol) in 7 mL of anhydrous DMF. Thecrude product was purified on a silica gel column eluting with 20% EtOAcin hexanes to give B7 in 34% (67 mg, 0.17 mmol) yield as a pale yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ=8.01 (d, J=8.3 Hz, 2H), 7.78 (d, J=8.0Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 3.91 (s, 3H),3.83 (d, J=7.2 Hz, 4H), 1.35 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=167.3,145.8, 143.4, 135.2, 130.0, 129.1, 128.3, 127.7, 84.0, 53.4, 52.8, 52.3,25.1. ESI-MS(+): m/z 382.03 [M+H]⁺.

Methyl4(((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)amino)methyl)benzoate(B8). In 5 mL of anhydrous DMF was dissolved methyl4-(aminomethyl)benzoate hydrochloride (65 mg, 0.32 mmol), B2a (100 mg,0.25 mmol), and Et₃N (105 μL, 0.75 mmol). The reaction was allowed tostir overnight at room temperature. The solvent was removed by rotaryevaporation and the residue was redissolved in EtOAc and washed threetimes with water and once with brine. The organic layer was dried overMgSO₄, filtered, and concentrated. Product was ran on a silica gelcolumn and eluted with 10% EtOAc in hexanes yielding B8 in 72% yield (77mg, 0.18 mmol). ¹H NMR (400 MHz, CDCl₃) δ=8.01 (d, J=7.3 Hz, 2H), 7.80(d, J=7.5 Hz, 1H), 7.36-7.33 (m, 4H), 5.15 (s, 2H), 4.44 (d, J=6.1 Hz,2H), 3.91 (s, 3H), 1.34 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=167.1,156.6, 143.8, 139.5, 135.2, 130.2, 129.6, 127.2, 126.4, 84.1, 67.1,52.4, 45.0, 25.1. ESI-MS(+): m/z 426.1 [M+H]⁺, 443.08 [M+NH₄]⁺.

Methyl2-(((((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)carbonyl)amino)methyl)benzoate (B9). In 5 mL of anhydrous DMF was dissolved2-carbomethoxybenzylamine hydrochloride (65 mg, 0.32 mmol) and B2a (100mg, 0.25 mmol) with triethylamine (105 μL, 0.75 mmol). The reaction wasallowed to stir at room temperature for 16 h. The solvent was removed byrotary evaporation and the residue was redissolved in EtOAc and washedwith a saturated solution of sodium bicarbonate. The organic layer wasdried over MgSO₄, filtered, and concentrated for purification via silicagel column chromatography eluting with 8% EtOAc in hexanes. B9 wascollected as a yellow oil in 63% yield (67 mg, 0.16 mmol). ¹H NMR (400MHz, CDCl₃) δ=7.9 (d, J=7.3 Hz, 1H), 7.77 (d, J=7.9 Hz, 2H), 7.57-7.46(m, 2H), 7.36 (td, J₁=8.8 Hz, J₂=1.8 Hz, 1H), 7.32 (d, J=7.9 Hz, 2H),5.9 (t, J=5.9 Hz, 1H, NH), 5.08 (s, 2H), 4.57 (d, J=6.7 Hz, 2H), 3.90(s, 3H), 1.33 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=162.3, 157.0, 140.1,139.6, 135.2, 133.3, 131.4, 128.2, 127.2, 126.4, 115.9, 84.2, 67.1,52.6, 44.7, 25.1. ESI-MS(+): m/z 425.81 [M+H]⁺, 442.72 [M+NH₄]⁺.

(4-(((2-Methyl-4-oxo-4H-pyran-3-yl)oxy)methyl)phenyl)boronic acid B10).2-Methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-4H-pyran-4-one(B10a) was synthesized as previously described. ¹B10a (200 mg, 0.58mmol) was dissolved in 20 mL of a 20% HCl aqueous solution and stirredvigorously for 3 h resulting in a thick, white slurry. The solids werefiltered off and washed with a large amount of water yielding B10 in 79%(13 mg, 0.05 mmol) yield as a white solid. ¹H NMR (400 MHz, DMSO) δ=8.06(s, 2H), 8.03 (dd, J₁=5.6 Hz, J₂=0.6 Hz, 1H), 7.76 (d, J=7.7 Hz, 2H),7.33 (d, J=7.8 Hz, 2H), 6.35 (dd, J₁=5.6 Hz, J₂=0.6 Hz, 1H), 5.01 (s,2H), 2.10 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ=176.3, 161.7, 155.5,143.6, 134.6, 133.9, 128.1, 116.3, 73.5, 13.8. ESI-MS(+): m/z 260.86[M+H]⁺.

(4-(((2-Oxopyridin-1(2H)-yl)oxy)methyl)phenyl)boronic acid (B11).1-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)pyridin-2(1H)-one(B11a) was synthesized as previously described. 1 B11a (200 mg, 0.61mmol) was dissolved in 20 mL of a 20% HCl aqueous solution and stirredvigorously for 3 h resulting in a thick, white slurry. The solids werefiltered off and washed with a large amount of water yielding B11 in 77%yield (115 mg, 0.47 mmol) as a white solid. 1H NMR (400 MHz, DMSO)δ=7.79 (d, J=7.9 Hz, 2H), 7.74 (dd, J1=7.1 Hz, J2=2.0 Hz, 1H), 7.41 (d,J=7.8 Hz, 2H), 7.39 (td, J1=7.9 Hz, J2=2.4 Hz, 1H), 6.54 (dd, J1=9.2 Hz,J2=1.6 Hz, 1H), 6.11 (td, J1=8.4 Hz, J2=1.7 Hz, 1H), 5.18 (s, 2H). 13CNMR (100 MHz, CDCl3) δ=160.0, 140.2, 137.3, 134.1, 129.1, 121.3, 106.4,78.7. ESI-MS (+): m/z 245.89 [M+H]+.

1,2-Dimethyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)pyridin-4(1H)-one(B12). The synthesis of B12 was accomplished following the procedureoutlined for B1 using 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (80 mg,0.54 mmol), 4-bromomethylphenyl boronic acid pinacol ester (180 mg, 0.59mmol), and K₂CO₃(223 mg, 1.6 mmol) in 8 mL of acetonitrile affording B12in 50% yield (0.09 g, 0.26 mmol). ¹HNMR (400 MHz, CDCl₃) δ=7.70 (d,J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.27 (d,J=7.6 Hz, 1H), 5.18 (s, 2H), 3.44 (s, 3H), 2.02 (s, 3H), 1.29 (s, 12H).¹³C NMR (100 MHz, CDCl₃) δ=173.55, 146.13, 141.63, 140.83, 139.19,134.91, 128.46, 117.21, 84.05, 73.00, 41.80, 24.97, 13.15. ESI-MS(+):m/z 356.20 [M+H]⁺, 378.10 [M+Na]⁺.

2-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)cyclohepta-2,4,6-trienone(B13). The synthesis of B13 was accomplished following the procedureoutlined for B1 using 2-hydroxycyclohepta-2,4,6-trienone (0.10 g, 0.82mmol), bromomethylphenyl boronic acid pinacol ester (0.27 g, 0.90 mmol),and K₂CO₃ (340 mg, 2.46 mmol) in 10 mL of acetonitrile affording B13 in60% yield (0.16 g, 0.48 mmol). ¹H NMR (400 MHz, CDCl₃) δ=7.81 (d, J=8Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.24-7.18 (m, 2H), 6.93 (td, J₁=9.6 Hz,J₂=1.2 Hz, 1H), 6.85-6.82 (m, 1H), 6.68 (d, J=9.6 Hz, 1H), 5.31 (s, 2H),1.34 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=180.94, 164.48, 138.63,137.62, 136.64, 135.41, 132.73, 128.50, 126.25, 115.09, 84.10, 70.96,25.08. ESI-MS(+): m/z 338.82 [M+H]⁺.

8-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)quinoline(B14). The synthesis of B14 was accomplished following the procedureoutlined for B1 using 8-hydroxyquinoline (0.12 g, 0.8 mmol),4-bromomethylphenyl boronic acid pinacol ester (0.26 g, 0.88 mmol), andK₂CO₃ (0.33 g, 2.4 mmol) in 10 mL of acetonitrile affording B14 in 22%yield (0.06 g, 0.17 mmol). ¹H NMR (400 MHz, CDCl₃) δ=8.96 (dd, J_(j)=4.4Hz, J₂=1.2 Hz, 1H), 8.09 (dd, J₁=8.4 Hz, J₂=1.6 Hz, 1H), 7.79 (d, J=7.6Hz, 2H), 7.49 (d, J=7.6 Hz, 2H), 7.40 (dd, J₁=8 Hz, J₂=4 Hz, 1H)7.34-7.28 (m, 2H), 6.95 (dd, 7.79 J₁=7.2 Hz, J₂=1.6 Hz, 1H), 5.47 (s,2H), 1.31 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=154.38, 149.60, 140.69,140.42, 136.13, 135.32, 129.70. 126.77, 126.26, 121.84, 120.11, 110.25,84.01, 70.87, 25.08. ESI-MS(+): m/z 362.02 [M+H]⁺.

N-(Quinolin-8-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanesulfonamide(B15). N-(quinolin-8-yl)methanesulfonamide was synthesized as previouslydescribed.² N-(quinolin-8-yl)methanesulfonamide (0.08 g, 0.34 mmol), wasreacted with 4-bromomethylphenyl boronic acid pinacol ester (0.11 g,0.37 mmol), in the presence of K₂CO₃ (0.14 g, 1.0 mmol) in 3 mL MeCN ina microwave reactor at 90° C. for 30 min affording B15 in 63% yield(0.09 g, 0.21 mmol). ¹H NMR (400 MHz, CDCl₃) δ=8.97 (dd, J₁=4 Hz, J₂=1.6Hz, 1H), 8.18 (dd, J₁=8.4 Hz, J₂=1.6 Hz, 1H), 7.74 (dd, J₁=8.4 Hz,J₂=1.2 Hz, 1H), 7.64 (d, J=8 Hz, 2H), 7.50 (dd, J₁=7.2 Hz, J₂=1.2 Hz,1H), 7.46 (dd, J₁=8.4 Hz, J₂=4.4 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.22(d, J=8 Hz, 2H), 5.20 (s, 2H), 3.20 (s, 3H), 1.30 (s, 12H). ¹³C NMR (100MHz, CDCl₃) δ=150.30, 145.18, 140.39, 137.00, 135.36, 135.17, 134.93,129.74, 129.06, 128.25, 126.75, 121.68, 83.98, 55.08, 40.37, 25.08.ESI-MS(+): m/z 438.96 [M+H]⁺, 460.97 [M+Na]⁺.

N-((4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzamide(B16). N-hydroxybenzamide (0.17 g, 1.2 mmol) was dissolved in 8 mL ofMeOH followed by the addition of 4-bromomethylphenyl boronic acidpinacol ester (0.40 g, 1.30 mmol). A 40% aqueous solution of NaOH (2 mL)was then added dropwise and the reaction was left to stir at refluxovernight. After cooling to room temperature and concentrated,concentrated HCl was added until a pH of 1 was observed. The resultingsolution was then extracted with EtOAc and washed with brine. Theorganic layer was collected and dried over MgSO₄ then purified viasilica gel chromatography affording B16 in 6% yield (0.03 g, 0.07 mmol).¹HNMR (400 MHz, CDCl₃) δ=8.61 (br, 1H, NH), 7.83 (d, J=8 Hz, 2H), 7.64(d, J=7.6 Hz, 2H), 7.51-7.37 (m, 5H), 5.04 (s, 2H), 1.35 (s, 12H). ¹³CNMR (100 MHz, CDCl₃) δ=166.67, 138.45, 135.32, 132.35, 132.10, 128.95,128.72, 127.25, 84.18, 78.45, 25.10. ESI-MS(+): m/z 354.10 [M+H]⁺,376.10 [M+Na]⁺.

N-([1,1′-biphenyl]-4-ylmethyl)-6-oxo-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-1,6-dihydropyridine-2-carboxamide(B17). 1,2-HOPO-2 was prepared as previously reported.^([11]).1,2-HOPO-2 (0.20 g, 0.6 mmol) was dissolved in 15 mL of anhydrous DMF.To this was added K₂CO₃ (0.26 g, 1.8 mmol) followed by4-bromomethylphenyl boronic acid pinacol ester (0.19 g, 0.6 mmol). Thereaction was heated overnight at 80° C. under nitrogen. After cooling toroom temperature, the solvent was evaporated and the resulting oil wasbrought up in dichloromethane (20 mL) then washed twice with H₂O (20 mL)and once with brine (20 mL). The organic layer was dried over MgSO₄,filtered and concentrated for silica gel column purification elutingwith 1% MeOH in DCM to yield a white solid in 44% yield (0.15 g, 0.27mmol). ¹H NMR (500 MHz, CDCl₃) δ=7.99 (br, 1H, NH), 7.77 (d, J=8.0 Hz,2H), 7.55 (d, J=7.45 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz,2H), 7.38 (d, J=8.0 Hz, 2H), 7.34 (t, J=7.45 Hz, 1H), 7.27-7.25 (m, 3H),6.64 (dd, J₁=9.15 Hz, J₂=1.7 Hz, 1H), 6.57 (dd, J₁=6.9 Hz, J₂=1.75 Hz,1H), 5.26 (s, 2H, OCH₂), 4.53 (d, J=5.75 Hz, 2H, NCH), 1.32 (s, 12H).¹³C NMR (100 MHz, CDCl₃) δ=160.2, 158.7, 142.2, 141.1, 140.8, 138.3,136.4, 136.0, 135.3, 129.6, 129.0, 128.7, 127.7, 127.6, 127.3, 124.6,107.2, 84.2, 79.4, 44.0, 25.1. ESI-MS(+): m/z 537.30 [M+H]⁺, 559.33[M+Na]⁺. Anal. calcd for C₃₂H₃₃BN₂O₅.0.25H₂O: C, 71.05; H, 6.24; N,5.18. Found: C, 71.41; H, 6.65; N, 5.50.

N-([1,1′-biphenyl]-4-ylmethyl)-4-oxo-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-4H-pyran-2-carboxamide(B18). PY-2 was prepared as previously reported.^([11]) Proinhibitor 2was synthesized and purified following the same procedure for 1 usingPY-2 (0.20 g, 0.6 mmol), Cs₂CO₃ (0.61 g, 1.8 mmol), and4-bromomethylphenyl boronic acid pinacol ester (0.37 g, 1.2 mmol) in 15mL of anhydrous DMF. ¹H NMR (400 MHz, CDCl₃) δ=8.13 (t, J=5.2 Hz, 1H,NH), 7.84 (d, J=5.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.61 (dd, J=8.4 Hz,J₂=1.2 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.37(dd, J=7.2 Hz, J₂=1.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 2H), 7.21 (d, J=8.0Hz, 2H), 5.39 (s, 2H, OCH₂), 4.47 (d, J=5.6 Hz, 2H), NCH₂), 1.33 (s,12H). ¹³C NMR (100 MHz, CDCl₃) δ=176.0, 159.0, 154.8, 147.2, 141.0,140.9, 137.9, 136.2, 135.6, 135.3, 129.0, 128.7, 128.6, 127.8, 127.6,127.4, 126.3, 117.8, 84.2, 75.4, 43.7, 25.1. ESI-MS(+): m/z 538.20[M+H]⁺, 560.26 [M+Na]⁺. Anal. calcd. for C₃₂H₃₂BNO₆.0.30H₂O: C, 70.81;H, 6.05; N, 2.58. Found: C, 71.18; H, 6.49; N, 2.60.

1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)pyridin-2(1H)-one(B19). 2-hydroxypyridine-1-oxide (0.04 g, 0.34 mmol) was dissolved in 5mL of anhydrous DMF. To this was added K₂CO₃ (0.14 g, 1.02 mmol) and4-bromomethylphenyl boronic acid pinacol ester (0.10 g, 0.34 mmol). Thereaction was heated to 80° C. and allowed to stir under nitrogenovernight. After cooling to room temperature, the solvent was evaporatedand the resulting residue was brought up in dichloromethane and washedtwice with water. The organic layer was dried over MgSO₄, filtered andconcentrated for purification via silica gel chromatography eluting with2% MeOH in DCM. The protected B19 was collected as an off-white solid in87% yield (98 mg, 0.3 mmol). ¹H NMR (400 MHz, CDCl₃) δ=7.79 (d, J=8.0Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.24 (td, J=7.2 Hz, J₂=2.0 Hz, 1H),7.05 (dd, J=7.2 Hz, J₂=2.0 Hz, 1H), 6.67 (dd, J=9.2 Hz, J₂=1.2 Hz, 1H),5.89 (td, J=6.8 Hz, J₂=1.6 Hz, 1H), 5.29 (s, 2H), 1.35 (s, 12H). ¹³C NMR(100 MHz, CDCl₃) δ=159.2, 138.9, 137.0, 136.8, 135.3, 129.5, 122.9,104.7, 84.3, 78.4, 25.1. ESI-MS(+): m/z 328.18 [M+H]⁺. Anal. calcd. forC₁₈H₂₂BNO₄. 0.4 CH₃OH: C, 65.26; H, 6.94; N, 4.16. Found: C, 65.54; H,7.20; N, 3.76.

2-methyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-4H-pyran-4-one(B20). Maltol (0.50 g, 3.96 mmol) was dissolved in 25 mL of acetonitrilefollowed by the addition of 1.6 g (11.88 mmol) of K₂CO₃. The reactionwas heated to reflux for 10 min before adding 4-bromomethylphenylboronic acid pinacol ester (1.3 g, 4.4 mmol). The reaction was leftstirring under refluxing conditions for 12 h then cooled to roomtemperature and filtered rinsing with DCM. The resulting filtrate wasconcentrated and purified via silica gel chromatography eluting with0-2% MeOH in DCM. B20 (1.03 g, 3.0 mmol) was collected and driedyielding a pale yellow solid in 76% yield. ¹H NMR (400 MHz, CDCl₃)δ=7.77 (d, J=7.6 Hz, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.37 (d, J=7.6 Hz,2H), 6.35 (d, J=5.6 Hz, 1H), 5.19 (s, 2H), 2.06 (s, 3H), 1.34 (s, 12H).¹³C NMR (100 MHz, CDCl₃) δ=175.3, 160.0, 153.6, 143.9, 140.0, 135.1,128.5, 117.4, 84.1, 73.6, 25.1, 15.2. ESI-MS(+): m/z 343.18 [M+H]⁺.Anal. calcd. for C₁₉H₂₃BO₅: C, 66.69; H, 6.77. Found: C, 66.34; H, 6.67.

4-nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbonate (B21a). 4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.5g, 2.1 mmol) was dissolved in 20 mL of dry THF. Triethylamine (0.6 mL,4.3 mmol) was added followed by 4-nitrophenyl chloroformate (0.47 g, 2.3mmol) and the reaction was allowed to stir at room temperature for 1 h.The reaction was diluted with ethyl acetate and washed with 1.0 M HClfollowed by saturated NaHCO₃. The organic layer was dried over MgSO₄,filtered and concentrated. Compound B21a was purified on a silica gelcolumn eluting with 5% EtOAc in hexanes to give 0.51 g (1.3 mmol, 60%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.25 (d, J=9.2 Hz,2H), 7.85 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=9.2 Hz,2H), 5.31 (s, 2H), 1.35 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=155.7,152.7, 145.6, 137.2, 135.4, 127.9, 125.5, 122.0, 84.2, 71.0, 25.1.ESI-MS(+): m/z 417.19 [M+NH₄]⁺, 422.20 [M+Na]⁺.

2-methyl-4-oxo-4H-pyran-3-yl4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonate (B21).Maltol (0.032 g, 0.25 mmol) was dissolved in 5 mL of dry DMF and K₂CO₃(0.10 g, 0.75 mmol) was added. The reaction was heated to 80° C. for 10minutes before adding B21a (0.10 g, 0.25 mmol). The reaction was allowedto go for 1.5 h. After cooling to room temperature, DMF was removed byrotary evaporation. The residue was brought up in EtOAc, washed withwater (3×) and with brine. The organics were dried over MgSO₄, filteredand concentrated for column purification. B21 was eluted with 1% MeOH inDCM giving a pale orange compound in 80% yield (0.078 g, 0.2 mmol). ¹HNMR (400 MHz, CDCl₃) δ=7.82 (d, J=8.0 Hz, 2H), 7.68 (d, J=6.0 Hz, 1H),7.41 (d, J=8.0 Hz, 2H), 6.43 (d, J=5.6 Hz, 1H), 5.30 (s, 2H), 2.30 (s,3H), 1.34 (s, 12H). ¹³C NMR (100 MHz, CDCl₃) δ=172.1, 159.6, 154.6,152.2, 139.3, 137.6, 135.3, 127.6, 117.3, 115.9, 84.2, 71.1, 25.1, 15.2.ESI-MS(+): m/z 387.07 [M+H]⁺, 409.13 [M+Na]⁺. Anal. calcd. forC₂₀H₂₃BO₇: C, 62.20; H, 6.00. Found: C, 61.85; H, 6.40.

Synthesis of Control Compounds

1-(benzyloxy)pyridin-2(1H)-one (7). 2-hydroxypyridine-1-oxide (0.50 g,4.5 mmol) was reacted with benzyl bromide (0.64 mL, 5.4 mmol) in DMF (10mL) in the presence of K₂CO₃ (1.8 g, 13.5 mmol) at 80° C. for 16 h.After cooling to room temperature, the solvent was removed by rotaryevaporation. The crude product was redissolved in DCM and washed twicewith water. The organic layer was then dried over MgSO₄, filtered, andconcentrated resulting in 7 as a white solid in 84% yield (0.78 g, 3.8mmol) without the need for further purification. ¹H NMR (400 MHz, CDCl₃)δ=7.41-7.36 (m, 5H), 7.25 (td, J₁=6.8 Hz, J₂=2.0 Hz, 1H), 7.10 (dd,J₁=7.2 Hz, J₂=2.0 Hz, 1H), 6.68 (dd, J₁=9.2 Hz, J₂=1.6 Hz, 1H), 5.91(td, J₁=6.8 Hz, J₂=1.6 Hz, 1H), 5.28 (s, 2H). ¹³C NMR (100 MHz, CDCl₃)δ=159.2, 138.9, 136.9, 133.9, 130.3, 129.6, 128.9, 122.9, 104.7, 78.6.ESI-MS(+): m/z 202.19 [M+H]⁺, 224.29 [M+Na]⁺.

3-(benzyloxy)-2-methyl-4H-pyran-4-one (7). To a 500 mL flask with 10.0 g(0.08 mol) of maltol (3-hydroxy-2-methyl-4H-pyran-4-one) in 120 mL ofanhydrous DMF was added 14.1 mL (0.12 mol) of benzyl bromide andpotassium carbonate (16.4 g, 0.12 mol) and heated at 80° C. overnight.After cooling to room temperature, the reaction was filtered and thesolvents evaporated. The residual oil was brought up in 100 mL CH₂Cl₂and washed twice with a saturated NaHCO₃ solution, water, and brine. Theorganic layer was dried over MgSO₄, filtered and concentrated. Productwas purified on a silica gel column eluting with 0.5% MeOH in CH₂Cl₂ toyield a pale yellow solid in 75% yield (12.8 g, 59 mmol). ¹H NMR (400MHz, CDCl₃) δ=7.59 (d, J=5.6 Hz, 1H), 7.36 (m, 5H), 6.36 (d, J=5.6 Hz,1H), 5.15 (s, 2H, OCH₂), 2.08 (s, 3H, CH₃). ESI-MS(+): m/z 217.03[M+H]⁺, 239.07 [M+Na]⁺.

Example 4 Exemplary Methods Related to Prodrugs Comprising CarbohydrateMoieties

UV-Vis Spectroscopy. Absorption spectra of compounds 1-8 were taken on aPerkin-Elmer Lambda 25 UV-visible spectrophotometer. To a 1.0 mLsolution at 0.05-0.06 mM concentration in HEPES buffer (50 mM, pH 7.5)was added β-glucosidase (16 U for compounds 2, 4, and 6, and 100 U forcompound 8). Spectra were monitored over time either at room temperaturefor compounds 1-7 or at 37° C. for compound 8.

Calculation of Km. To a 1.0 mL solution of 8 in HEPES buffer at 25 μM,50 μM, 75 μM, 100 μM, and 200 μM was added 100 U of β-glucosidase.Spectra were monitored over 4 h at 37° C. The concentration of productformed, 1,2-HOPO-2 (7), was determined using the extinction coefficientfor 7 calculated at 346 nm (4279±372 M-1 cm-1) and was plotted versustime (min). The initial velocity (ν) of each reaction was determinedanalyzing the linear slope of the first 50 min. The Km value wascalculated from the Lineweaver-Burk plot (1/ν vs. 1/[8]) where −1/Kmequals the x-intercept (FIG. 10).

Acid Stability. To examine the stability of compound 8 towards acidhydrolysis, the absorption spectra of a 0.05 mM solution of 8 in a 0.1 Maqueous solution of HCl was collected. Spectra were collected at roomtemperature every hour for a 24 h time period. No change in the spectrawas observed (FIG. 11).

HPLC. Analytical HPLC was performed on a HP Series 1050 system equippedwith a Vydac® C18 reverse phase column (218TP, 250×4.6 mm, 5 μm).Separation was achieved with a flow rate of 1 mL/min and the followingsolvents: solvent A is 5% MeOH and 0.1% formic acid in H₂O and solvent Bis 0.1% formic acid in MeOH. Starting with 95% A and 5% B, an isocraticgradient was run for 15 min to a final solvent mixture of 5% A and 95%B, which was held for 5 min before ramping back down to 95% A and 5% Bin 2 min and holding for an additional 4 min. Compounds 1-6 wereprepared in HEPES buffer (50 mM, pH 7.5) at a concentration of 1.6 mMand compounds 7-8 were prepared at a concentration of 1 mM. Retentiontimes of compounds 1-8 were determined under identical HPLC conditionsprior to evaluation of glucose cleavage of the protected compounds. Toevaluate the efficiency of glucose cleavage for the protected ZBGs 2, 4,and 6, 1 mL samples of each compound were made up at a concentration of1.6 mM in HEPES buffer (50 mM, pH 7.5). To each sample was added 50 U ofβ-glucosidase (1 U/μL) and incubated at 37° C. After 1 h, a 400 μL,aliquot was collected and filtered through a microcentrifuge filter (30kDa MWCO, PLTK cellulosic membrane) to remove β-glucosidase prior toinjection on the HPLC. For the full-length inhibitor 8, a 1 mL sample inHEPES buffer at a concentration of 1 mM was incubated at 37° C. with 250U of β-glucosidase (1 U/μL) for 5 h. A 200 μL, aliquot was collectedevery hour and filtered through a microcentrifuge filter prior toinjection on the HPLC.

Inhibition Assays. MMP-9 (catalytic domain, human, recombinant), MMP-8(catalytic domain, human, recombinant), and the assay kit were purchasedfrom BIOMOL International. The assays were carried out according to theprocedure provided with the kit. MMP activity was measured in 96-wellplates using a Bio-Tek Flx 800 fluorescent plate reader. The ZBGs andtheir protected analogs were dissolved in DMSO and diluted in HEPESbuffer (50 mM, pH 7.5) to a concentration of 10 mM for 1-2, 40 mM for3-4, and 1.25 mM for 5-6. Each well contained 20 μL, of MMP-9 (0.45U/mL), inhibitor (10 μL, of 1-6), 5 μL, of β-glucosidase (1 U/μL) whenused, and buffer for a total volume of 99 μL. These were incubated for 1h at 37° C. A control sample containing just β-glucosidase (5 μL at 5U/μL) with MMP-9 (20 μL) was also prepared to confirm that theβ-glucosidase did not inhibit of MMP-9. The reaction was initiated bythe addition of 1 μL (400 μM) of the fluorescent substrate(Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 whereMca=(7-methoxycoumarin-4-yl)-acetyl andDpa=N-3-(2,4-dinitrophenyl)-L-α-β-diaminopropionyl)) and kineticactivity was measured every minute for 30 min with excitation andemission wavelengths at 335 nm and 405 nm, respectively. Enzyme activitywith inhibitor was calculated with respect to the control experiment (noinhibitor present). Measurements were performed in duplicate in twoindependent experiments.

For Cmpds 7 and 8, 1 mL sample in HEPES buffer at a concentration of 1mM was incubated at 37° C. with 250 U of β-glucosidase (1 U/μL) for 4 hgiving a final concentration of 0.8 mM of the inhibitor. After 4 h, a200 μL aliquot was collected and filtered through a microcentrifugefilter. UV-Vis absorption spectroscopy was to verify that theconcentration of 1,2-HOPO-2 was 0.71±0.2 mM in each of the samples usingthe extinction coefficient for 1,2-HOPO-2 (7) calculated at 346 nm(4,279.3±372 M-1 cm-1). Each well was made up with 20 μL of MMP-9 (0.45U/mL), inhibitor (2 μL, for 7 and 8), and buffer for a total volume of99 μL. These were incubated for 30 min at 37° C. For MMP-8 inhibitionassays, each of the samples was diluted to 1 μM in HEPES buffer and 15μL of each were added to 20 μL of MMP-8 (0.092 U/mL) and buffer for atotal of 99 μL. The reaction was initiated by the addition of 1 μL (400μM) of the fluorescent substrate and kinetic activity was measured everyminute for 30 min with excitation and emission wavelengths at 335 nm and405 nm, respectively. Enzyme activity with inhibitor was calculated withrespect to the control experiment (no inhibitor present). A controlsample was also performed, in which an aliquot of 250 U of β-glucosidase(1 U/μL) with 1 mL of HEPES buffer was incubated for 4 h at 37° C.,filtered through a microcentrifuge filter, and evaluated in the MMPassay to confirm that no inhibition is observed with β-glucosidase.Measurements were performed in duplicate in two independent experiments.

IC50 values were obtained for compounds 1-8 against MMP-9 and forcompounds 7 and 8 against MMP-8. Serial dilutions of the compounds inDMSO were incubated at 37° C. for 30 minutes with 20 μL of theappropriate MMP (0.45 U/mL for MMP-9 and 0.092 U/mL for MMP-8) and HEPESbuffer (50 mM, pH 7.5) for a total volume of 99 μL. The reaction wasinitiated by the addition of 1 μL (400 μM) of the fluorescent substrateand kinetic activity was measured every minute for 20 min withexcitation and emission wavelengths at 335 nm and 405 nm, respectively.Enzyme activity with inhibitor was calculated with respect to thecontrol experiment (no inhibitor present). Measurements were performedin duplicate. The percent inhibition is plotted versus the inhibitorconcentration. A linear fit of the data for each experiment gives the1050 value of the inhibitor where y=50%.

Example 5 Exemplary Prodrugs Comprising a Carbohydrate Moiety

Building on the strategy of glycosidic protecting groups, we firstfocused our attention on the development of glucose-protectednon-hydroxamate zinc-binding groups (ZBGs)^(32,33) that can be activatedby enzymatic cleavage of the protecting group with β-glucosidase torelease the ZBG and glucose (FIG. 1). The synthesis of the protectedZBGs (2, 4, and 6) was accomplished following a literature procedureused by Orvig and coworkers for enzyme-activated metal-binding chelators(Scheme 1 following).^(9,34). The ZBG was protected withacetobromo-α-D-glucose in a 1:1 solution of 1.0 M NaOH and CH₂Cl₂ in thepresence of (nBu)₄NBr. The desired products were obtained by cleavage ofthe glucose acetate groups using NaOMe in MeOH.

The conditions for Scheme 1 are the following: (i)acetobromo-α-D-glucose, tetrabutylammonium bromide, CH2Cl2:1.0 M NaOH(1:1), 3 h, room temp; (ii) NaOMe, MeOH, 2-3 h, room temp; (iii) P4S10,HMDO, benzene, 100° C., 45 min.

To evaluate the ability of these compounds to be enzymaticallyactivated, cleavage of the protected ZBGs in the presence ofβ-glucosidase (from almond extract, Fluka) was followed using electronicspectroscopy. To a solution of the protected ZBG in HEPES buffer wasadded β-glucosidase and the change in absorbance was monitored overtime. As can be seen in FIG. 2 for compound 2, the absorbance over timeshows a decrease at 292 nm while a band at 312 nm emerges, indicative ofthe deprotected ZBG 1-hydroxy-2-pyridin-2(1H)-one (1). Similar spectrawere observed for the hydroxypyrone derivatives 4 and 6 (FIGS. 3-4). Inaddition, cleavage of the protected ZBGs was confirmed by HPLC analysis(FIGS. 5-7). These studies demonstrate that in aqueous buffer at roomtemperature, the glucose-protected ZBGs can be readily activated in thepresence of β-glucosidase providing compelling evidence thathydroxypyridinone and hydroxypyrone ZBGs are well suited for thedevelopment of enzyme-activated MMP proinhibitors.

Having demonstrated the use of glucose as an effective protecting groupfor the aforementioned ZBGs, we aimed to incorporate a glucoseprotecting group into a full-length MMPi (matrix metalloproteaseinhibitor) to develop an MMP proinhibitor. We selected the full-lengthinhibitor 1,2-HOPO-2 (7), a potent non-hydroxamate inhibitor of MMPsthat uses a 1-hydroxy-2-pyridin-2(1H)-one (1) ZBG.³⁵ Synthesis of theMMP proinhibitor was achieved by addition of acetobromo-α-D-glucose andCs₂CO₃ to 7 in DMF at room temperature to give 8a in high yields (>80%,Scheme 2). These reaction conditions were a vast improvement in yieldover the aqueous reaction conditions used to protect the ZBGs.Surprisingly, these high-yield reaction conditions did not produce thedesired products with the ZBGs (1, 3, and 5). The final proinhibitor (8)was obtained by deprotection of the glucose acetate groups with NaOMe inMeOH at 0° C. for one hour.

The MMP proinhibitor 8 was first evaluated for activation byβ-glucosidase using electronic spectroscopy and HPLC analysis (FIGS.8-9). Results from these studies indicate that while cleavage of 8 toproduce the active MMPi 1,2-HOPO-2 (7) goes to completion, the kineticsof the reaction are noticeably slower than that observed for theprotected ZBGs. Complete conversion of 8 to 7 required ˜4 h at 37° C.; aK_(m) value of 210 μM was determined (FIG. 10). Notably, compound 8 wasnot cleaved under acidic conditions (0.1 M HCl) over 24 h (FIG. 11).Overall, this is the first example of a glucosidase proinhibitor thatcan be enzymatically cleaved to yield the active MMPi.

The ability of the protected compounds to inhibit MMP-9 (gelatinase-B)in the presence of β-glucosidase was evaluated using afluorescence-based assay.³⁶. Compounds 1-8 were evaluated at aconcentration close to their reported IC₅₀ values in the presence andabsence of β-glucosidase (FIG. 12). The percent inhibition of MMP-9 withthe ZBGs (1, 3, and 5) is close to 50% when tested with and withoutβ-glucosidase indicating that the presence of low concentrations ofβ-glucosidase in the assay has little effect on MMP inhibition. Theprotected ZBGs (2, 4, and 6) show attenuated inhibition when evaluatedwithout the activating enzyme and complete restoration of inhibitionwhen exposed to β-glucosidase. Compounds 2, 4, and 6 do show someinhibition of MMP-9 which is likely due to non-specific binding at thehigh concentrations of the ZBGs (0.125-4 mM) used in these experiments.

In the absence of β-glucosidase, the complete MMPi 8 (16 μM) displaysvery little inhibition of MMP-9, but upon activation, MMP-9 activity isinhibited by 73%, which is essentially identical to an authentic sampleof inhibitor 7. Even greater potency was observed against MMP-8, whereMMPi 8 could be activated with β-glucosidase to obtain 33% inhibition atonly 150 nM (FIG. 11), representing a >1000-fold increase in activityupon enzymatic activation. The factor of 1000 difference in the quotientIC₅₀ (IC₅₀ value of proinhibitor in the presence and absence of enzyme)has been reported as an optimal value for the ADEPT approach to targetedtherapy,¹¹ and hence MMPi 8 exceeds this threshold with MMP-8. Thehigher activity against MMP-8 is consistent with the potency of thecleavage product (7) against this metalloenzyme.³⁵ The results for 8show that incorporation of a ZBG protection strategy into an MMPi givesnear complete abolition and recovery of inhibitory activity with theseenzyme inhibitors.

In summary, there has been demonstrated passivation of an MMPi as aproinhibitor, activation thereof through an enzymatic reaction, andinhibition of MMPs in a controlled manner. We have shown that protectionof the metal-binding moiety of MMPi can be achieved and enzymaticallyremoved to release an active, intact MMPi.

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Example 6 Exemplary Methods Related to Prodrugs Including SulfonateEster Moieties

Proinhibitors for matrix metalloproteinases (MMPs), as described herein,have been synthesized. Specifically, MMP proinhibitors have beenobtained that can be activated in the presence of reactive oxygenspecies (ROS). These findings show that the resultant compounds can berapidly cleaved by ROS and hence may provide cardioprotection at anischemic site. There is provided description of the use of two differentROS-activated protecting groups (aryl sulfonate esters and boronicesters) with the zinc-binding group (ZBG) warheads of MMP inhibitors.

General. Starting materials and solvents were purchased from commercialsuppliers (Sigma-Aldrich, Alfa Aesar, Fisher, and others) and used asreceived. ¹H/¹³C NMR spectra were recorded at ambient temperature on a400 or 500 MHz Varian FT-NMR instrument or a 500 MHz JEOL instrument,located in the Department of Chemistry and Biochemistry at theUniversity of California San Diego. Mass spectra were obtained at theMolecular Mass Spectrometry Facility in the Department of Chemistry andBiochemistry at the University of California, San Diego. Elementalanalysis was preformed by NuMega Resonance Labs, San Diego.

UV-Vis Spectroscopy. Absorption spectra of compounds were taken on aPerkin-Elmer Lambda 25 UV-Visible Spectrophotometer. To a 1.0 mLsolution at 0.05 mM concentration of each compound in HEPES buffer (50mM, pH 7.5) was added H₂O₂ (10 μL, 0.09M in HEPES) and absorptionspectra were monitored over time at room temperature. Hydrolyticstability was measured by monitoring each sample in HEPES buffer over a24 hour time period.

Calculation of Rate Constant. The pseudo-first order rate constant wascalculated following literature procedure [20]. To a 1.0 mL solution ofcompounds PZBG-1a, PZBG-1b, PZBG-1e, PZBG-5a, and PZBG-5b in HEPESbuffer at 50 μM was added H₂O₂ to final concentrations of 150 μM, 250μM, 500 μM, 750 μM, and 900 μM. Spectra were monitored over 15-30 min atroom temperature with at least 50 spectra recorded at everyconcentration. The change in absorption at 298 nm for PZBG-1a andPZBG-1b were monitored, while the change in absorption at 288 nm wasrecorded for PZBG-1e, and 310 nm for PZBG-5a and PZBG-5b. The rateconstant (k_(obs)) was found from the linear slope of ln[(A-A_(ZBG))/(A_(o)-A_(ZBG))] vs. time where A_(ZBG) is the absorbanceof a 50 μM sample of the ZBG or full-length inhibitor and A_(O) is theinitial absorbance of PZBG-1a, PZBG-1b, PZBG-1e, PZBG-5a, and PZBG-5b.The rate of conversion was determined from the slope of the line ofk_(obs) vs. [H₂O₂].

HPLC. Analytical HPLC was performed on a HP Series 1050 system equippedwith a Vydac® C18 reverse phase column (218TP, 250×4.6 mm, 5 μm).Separation was achieved with a flow rate of 1 mL/min and the followingsolvents: solvent A is 5% MeOH and 0.1% formic acid in H₂O and solvent Bis 0.1% formic acid in MeOH. Starting with 95% A and 5% B, an isocraticgradient was run for 15 min to a final solvent mixture of 5% A and 95%B, which was held for 5 min before ramping back down to 95% A and 5% Bin 2 min and holding for an additional 4 min. Compounds ZBG-1a andPZBG-1a were prepared in HEPES buffer (50 mM, pH 7.5) at a concentrationof 1 mM and retention times were determined. To evaluate cleavage byH₂O₂, a 1 mM solution of PZBG-1a in HEPES buffer was reacted with a20-fold excess of H₂O₂ before analyzing under identical HPLC conditionsas before.

Inhibition Assays. MMP-12 (catalytic domain, human recombinant) waspurchased from Enzo Life Sciences. The assays were carried out in a96-well plate using a Bio-Tex Flx 800 plate reader. The activity ofMMP-12 was evaluated after a 30 min incubation in the presence of H₂O₂and proMMPi. The concentration of proMMPi used was selected to be closeto the IC₅₀ value of the parent full-length inhibitors, 1,2-HOPO-2 andPY-2[38]. In each well, 1 μL of proinhibitors PZBG-5a, PZGB-5b, andPZBG-6a and the inhibitors 1,2-HOPO-2 and PY-2 in DMSO (5 μM) wereincubated for 30 min at 37° C. with 20 μL of MMP-12 (0.35 U/mL), 10 μLH₂O₂ (1 mM in HEPES buffer, pH 7.5), and MMP assay buffer (50 mM HEPES,10 mM CaCl₂, 0.10% Brij-35, pH 7.5) for a total volume of 99 μL. Acontrol sample containing 10 μL H₂O₂ (1 mM in HEPES buffer, pH 7.5) inMMP assay buffer was also prepared to confirm that H₂O₂ did not inhibitMMP-12. The reaction was initiated by the addition of 1 μL (400 μM) ofthe fluorescent substrate (Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂ whereMca=(7-methoxycoumarin-4-yl)-acetyl andDpa=N-3-(2,4-dinitrophenyl)-L-α-β-diaminopropionyl)) after the 30 minuteincubation period and kinetic activity was measured every minute for 20minutes with excitation and emission wavelengths at 335 nm and 405 nm,respectively. Enzyme activity with inhibitor was calculated with respectto the control experiment—no inhibitor present. Measurements wereperformed in duplicate in two independent experiments.

(1 mM

Example 7 Exemplary Prodrugs Including Sulfonylaryls/Sulfonate Esters

Assessment of Sulfonate Esters as Suitable Protecting Groups for ZBGs.Previous studies utilizing fluorescent probes have shown sulfonateesters to be suitable protecting groups of hydroxyl groups that show aturn-on response upon exposure to ROS, including H₂O₂ and superoxideanion [35-37]. To investigate the use of sulfonate ester protectinggroups for the development of ROS-activated proMMPi, a small library ofcompounds was synthesized. As shown in FIG. 13, sulfonate esters withvarying substituents were appended to 1,2-hydroxypyridinone (1,2-HOPO,ZBG-1), 3-hydroxy-2-methyl-4H-pyran-4-one (maltol, ZBG-2),3-hydroxy-1,2-dimethylpyridin-4(1H)-one (3,4-HOPO, ZBG-3), and tropolone(ZBG-4) to evaluate which protected ZBGs provided efficient activationin the presence of H₂O₂. These protected ZBGs (PZBGs) were readilyprepared by combining a ZBG with the appropriate sulfonyl chloride inpyridine. In total, 17 PZBGs (1a-e, 2a-d, 3a-d, and 4a-d) were preparedand tested for cleavage in the presence of H₂O₂.

To evaluate cleavage of the compounds by ROS, a sample of each PZBG inHEPES buffer (50 mM, pH 7.5) was activated with excess H₂O₂ (0.9 M, 18equiv) and the change in absorbance was monitored over time viaelectronic spectroscopy. Surprisingly, only compounds derived from ZBG-1(1,2-HOPO) showed a change in absorption (corresponding to the formationof the free ZBG) upon exposure to H₂O₂. The fact that only the fivePZBG-1 derivatives (out of 17 total combinations) were cleaved in thepresence of H₂O₂ suggests that the N—O group is important for theobserved reactivity. FIG. 14 shows representative absorption spectra ofPZBG-1a in the presence of H₂O₂. A decrease in absorption at 298 nm overtime is noted, representing the disappearance of the PZBG-1a and agradual increase in absorption at 312 nm is observed, indicating theemergence of ZBG-1. In addition, analytical HPLC was used to confirmthat ZBG-1 was the product after reaction with H₂O₂ (FIG. 14). Upon theaddition of H₂O₂ to PZBG-1a for 60 min, a peak with a retention time of5.0 min was observed, which is identical to an authentic sample ofZBG-1. Similarly, treatment of PZBG-1b with H₂O₂ resulted in nearlyidentical spectra as found with PZBG-1a, while PZBG-1c showed rapidhydrolysis upon the addition of H₂O₂ (data not shown). It should benoted that the absorption spectra of PZBG-1d was not readilyinterpreted, due to the overlapping of absorption profiles of theprotecting group and the free ZBG; however, thin-layer chromatographyshowed the emergence of the free ZBG, demonstrating rapid hydrolyticcleavage of the protecting group (even in the absence of H₂O₂). Thesefindings taken together prompted the synthesis of PZBG-1e, a morewater-soluble alternative to PZBG-1c, with a carboxylic acid attached tothe para position of the sulfonate ester. A substantial increase insolubility in buffered solution was noted, and the cleavage behavior wassimilar to the other compounds reported (see below), making PZBG-1e anattractive candidate for development into a full length proMMPi. Asmentioned above, sulfonate ester derivatives of ZBG-2a-d, ZBG-3a-d, andZBG-4-a-d did not show any change in absorbance over a period of 1 hwith an 18 molar excess of H₂O₂. These findings suggest that the N—Obond in ZBG-1 is important for facile cleavage of the sulfonate estergroup in this series of ligands, although this will require verificationby additional studies. It is interesting to note that the compoundstested that did not contain the N—O moiety (those based off of PZBG-2,PZBG-3, and PZBG-4) appeared to be stable in aqueous buffer (over atleast a 1 h time period).

One key factor for any prodrug approach is the stability of theprotecting group in the absence of the triggering stimuli. In order totest the stability of the sulfonate esters in buffer, absorption spectrafor PZBG-1a, b, and e were collected over 24 h. These stability studiesshowed ˜50% cleavage of PZBG-1a and PZBG-1e in 6 h, while PZBG-1b was˜30% cleaved in 24 h. The rates of conversion of PZBG-1a, b, and e weredetermined by monitoring the change in absorption using pseudo-firstorder reaction conditions with an excess of H₂O₂ as previously reported[20]. The calculated rate constants indicate that PZBG-1e had thefastest rate constant at 1.3 M⁻¹ sec⁻¹, while rate constants of 0.7 M⁻¹sec⁻¹ and 0.3 M⁻¹ sec⁻¹ were determined for PZBG-1a and b, respectively.It should be noted that the determined rate constants do take intoaccount background hydrolysis and reactivity with H₂O₂; however, allkinetic experiments were taken over a 15-30 min time period, which isbefore a measurable amount of hydrolysis was observed. Experiments withPZBG-1c and PZBG-1d showed the fastest cleavage kinetics upon exposureto H₂O₂, with complete dissociation achieved in <3 min (no rateconstants determined). The rates of conversion for the PZBG-1 compoundsare consistent with the nature of the respective substituents on theleaving groups. When substituents are varied on an aromatic ring, thechange in free energy of activation for a given reaction is proportionalto the change in Gibbs free energy, as summarized by the Hammettequation [39]. Of the molecules for which rate constants were obtained,PZBG-1e that contains an electron-withdrawing group (—CO₂H) in the paraposition, dissociates the fastest. PZBG-1b, on the other hand, with anelectron-donating group (—CH₃) in the para position had the slowest rateof the compounds tested. PZBG-1a, with no substituents had a cleavagerate falling between the others, consistent with the Hammettrelationship. The results with PZBG-1c and PZBG-1d are also consistentwith this relationship, with the strongly electron withdrawing nitrogroups producing the fastest rates, resulting in the inability toacquire precise values.

Development of full-length proMMPi. Having demonstrated the ability ofsulfonate esters to act as cleavable protecting groups for ZBG-1, thischelator was incorporated into a full-length proMMPi. The correspondingfull-length inhibitor of ZBG-1 with a hydrophobic biphenyl backbone,1,2-HOPO-2, has been previously prepared and studied [38]. 1,2-HOPO-2 isan effective inhibitor of MMP-3, MMP-8 and MMP-12 with IC₅₀ values under100 nM [38]. Two full length MMPi (1,2-HOPO-2 and PY-2) were prepared bypreviously reported procedures and then protected in pyridine with anexcess of the appropriate sulfonyl chloride to generate proMMPi PZBG5a,PZBG5b, and PZBG6a. The products were generally purified via silica gelchromatography affording the desired product. The proMMPi PZBG5a andPZBG5b were evaluated for activation by H₂O₂ via electronic spectroscopyin the same manner as with the PZBG compounds. As shown in FIG. 15(Top), the activation of PZBG5a and PZBG5b to the known MMPi 1,2-HOPO-2is achieved upon the addition of H₂O₂. FIG. 16 shows the absorptionspectra of PZGB5b in which a decrease at 310 nm over time is observed,indicating the disappearance of the protected MMPi while a gradualincrease in absorption at 350 nm is observed, demonstrating theemergence of 1,2-HOPO-2. Pseudo-first order rate constants weredetermined with an excess of H₂O₂ as described above. Rate constants of0.3 M⁻¹ s⁻¹ and 1.1 M⁻¹ s⁻¹ were obtained for PZBG5a and PZBG5,respectively, which is in good agreement with the rate constantsdetermined for the protected chelators PZBG-1a and PZBG-1e. To evaluatethe stability of the sulfonate esters, absorption spectra of PZBG5a andPZBG5 were collected in buffer alone. Compounds PZBG5a and PZBG5 showed˜50% hydrolysis after 9 h and 3 h, respectively.

In order to further confirm that the behavior of the protected chelators(PZBG) was readily translated to a complete proMMPi, a proinhibitorbased on PZBG-2a was synthesized. Compound PZBG6a, which contains abiphenyl backbone like PZBG5a, was prepared. Upon cleavage of theprotecting group, PZBG6a should produce PY-2, a known inhibitor ofseveral MMPs [38]. Treatment of PZBG6a with excess H₂O₂ over the courseof 60 min did not result in cleavage of the sulfonate ester (Scheme 1),as evidenced by absorption spectroscopy (data not shown). This negativeresult is consistent with all of the findings described above, showingthat the cleavage behavior of the PZBG is retained in its full-lengthproMMPi.

MMP Inhibition Studies. To monitor the ability of the protectedcompounds to inhibit MMP-12 in the presence of H₂O₂, afluorescence-based assay was used [40]. Compounds PZBG-5a, PZBG-5b, andPZBG-6a were tested at concentrations close to the IC₅₀ values of theiractive parent molecules, 1,2-HOPO-2 and PY-2, against MMP-12. Thepercent inhibition of proinhibitors PZBG-5a, PZBG-5b, and PZBG-6aat 50nM were evaluated after 30 min of incubation with and without H₂O₂ (FIG.17). Before treatment with H₂O₂, PZBG5a and PZBG5 were shown to exhibit˜20% and ˜30% inhibition of MMP-12, respectively. This significant levelof inhibition is likely due to the hydrolysis of these compounds to theactive MMPi during the incubation period, as described in the stabilitystudies above. In addition, the inhibition assays are performed at ahigher temperature then our kinetic experiments, which may result in anincrease in the rate of hydrolysis and therefore lead to higherinhibition than might otherwise be expected. After treatment with 100 μMH₂O₂, the percent inhibition by proinhibitors PZBG5a and PZBG5 increasedto ˜30% and ˜50% respectively, indicative of activation to 1,2-HOPO-2.Proinhibitor PZBG6a was used as a negative control, and as expected,displayed no significant change in inhibitory activity upon exposure toH₂O₂.

In an effort to develop broadly applicable methods to metalloproteinprodrugs, we have focused on developing ‘proinhibitors’ of thezinc(II)-dependent matrix metalloproteinases (MMPs), a canonicalmetalloprotein target of medicinal interest.^(11, 12) MMP inhibitors(MMPi), like most metalloprotein inhibitors, generally employ ametal-binding group (MBG), which if blocked abolishes inhibitoryactivity. Prodrug matrix metalloproteinase inhibitors (‘proMMPi’) havebeen developed using enzymatic activation or activation by reactiveoxygen species (ROS).¹³⁻¹⁵ The development of ROS-activated proMMPiproved particularly intriguing, because: a) these were the firstROS-activated prodrugs of any kind reported, and b) these proMMPi cansimultaneously result in targeted delivery of an MMPi while scavengingtissue-damaging ROS.¹⁵ This ‘dual mode’ of action is particularlyrelevant to ischemia-reperfusion injury associated with stroke, where anincrease in ROS (e.g. H₂O₂) and the concurrent activation of MMPs duringthe inflammatory response leads to the breakdown of the protectiveblood-brain barrier.¹⁶⁻¹⁸

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Example 8 Exemplary Methods Related to Oxidatively-Sensitive Prodrugs

UV-Vis Spectroscopy. Absorption spectra of compounds B1-B16 were takenon a Perkin-Elmer Lambda 25 UV-visible spectrophotometer. To a 1.0 mLsolution at 0.05 mM concentration in HEPES buffer (50 mM, pH 7.5) wasadded H₂O₂ (10 uL (0.09 M) in HEPES for compounds B1-B12 and B14-B16, 10uL (0.9 M) in HEPES for compound B3, and 2.8 uL (0.09 M) in HEPES forcompound B13). Spectra were monitored over time at room temperature.Absorption spectra of compounds B17-B21 were taken on a Perkin-ElmerLambda 25 UV-visible spectrophotometer. To a 1.0 mL solution at 0.05 mMconcentration of compounds 1-7 in HEPES buffer (50 mM, pH=7.5) was addedH₂O₂ (10 uL, 0.09 M in HEPES) or KO₂ (0.10 mM) with catalase (5 U).Hydrolytic stability was measured by monitoring samples of B19-B21 inHEPES buffer for a 24 h time period. Spectra were monitored over time atroom temperature.

Calculation of Rate Constant. The pseudo-first order rate constant wascalculated by monitoring the absorption spectra over time in thepresence of excess hydrogen peroxide. To a 1.0 mL solution of compoundsB1-B3 and B10-B14 in HEPES buffer (50 mM, pH 7.5) at 50 μM was addedH₂O₂ to final concentrations of 150 μM, 250 μM, 500 μM, 750 μM, and 900μM. Spectra were monitored over 15-30 min at room temperature with atleast 50 spectra recorded. The change in absorption at 302 nm for B1-B3,272 nm for B10, 312 nm for B11, 268 for B12, 306 nm for B13, and 303 nmfor B14 were monitored. For compounds B1-B3 and B10-B11, the rateconstant (k_(obs)) was found from monitoring the appearance of themonitored absorption peak by plotting the linear slope of ln[(A_(∞)−A_(t))/(A_(∞))] vs. time (where A_(∞) is the absorbance of a 50μM sample of the methyl salicylate for B1-B3, maltol for B10, and1,2-HOPO for B11). For compounds B12-B14 the rate constant (k_(obs)) wasfound from monitoring the disappearance of the monitored absorption peakby plotting the linear slope of ln [(A−A_(ZBG))/(A₀−A_(ZBG))] vs. time(where A_(ZBG) is the absorbance of a 50 μM sample of the ZBG and A₀ isthe initial absorbance of B3-B5).³ The rate of conversion was determinedfrom the slope of the line of k_(obs) vs. [H₂O₂]. The pseudo-first orderrate constant was calculated following literature procedure.^([15]) To a1.0 mL solution of compounds B19-B21 in HEPES buffer at 50 μM was addedH₂O₂ to final concentrations of 150 μM, 250 μM, 500 μM, 750 μM, and 900μM. Spectra were monitored over 15-30 min at room temperature with atleast 50 spectra recorded. The change in absorption at 292 nm for B19and 252 nm for B20 and B21 were monitored. The rate constant (k_(obs))was found from the linear slope of ln [(A-A_(ZBG))/(A₀-A_(ZBG))] vs.time (where A_(ZBG) is the absorbance of a 50 μM sample of the ZBG andA₀ is the initial absorbance of B19-B21). The rate of conversion wasdetermined from the slope of the line of k_(obs) vs. [H₂O₂].

HPLC. Analytical HPLC was performed on a HP Series 1050 system equippedwith a Vydac® C18 reverse phase column (218TP, 250×4.6 mm, 5 μm).Separation was achieved with a flow rate of 1 mL/min and the followingsolvents: solvent A is 5% MeOH and 0.1% formic acid in H₂O and solvent Bis 0.1% formic acid in MeOH. Starting with 95% A and 5% B, an isocraticgradient was run for 15 min to a final solvent mixture of 5% A and 95%B, which was held for 5 min before ramping back down to 95% A and 5% Bin 2 min and holding for an additional 4 min. Compounds were prepared inHEPES buffer (50 mM, pH 7.5) at a concentration of 1 mM. Retention timesof compounds were determined under identical HPLC conditions prior toand after reaction with H₂O₂. LC-MS(+) was performed on compounds B6,B15 and B16 to confirm cleavage of the boronic ester to the phenolicmoiety.

Inhibition Assays. MMP-9 (catalytic domain, human, recombinant) andMMP-12 (catalytic domain, human, recombinant) were purchased from EnzoLife Sciences. The assays were carried out in 96-well plates using aBio-Tek Flx 800 plate reader. IC₅₀ values were obtained forproinhibitors B17 and B18 against MMP-9 and MMP-12. Serial dilutions ofthe compounds dissolved in DMSO were incubated at 37° C. for 30 minuteswith 20 μL of the appropriate MMP (0.45 U/mL for MMP-9 and 0.35 U/mL forMMP-12) in MMP assay buffer (50 mM HEPES, 10 mM CaCl₂, 0.10% Brij-35, pH7.5), for a total volume of 99 pt. The reaction was initiated by theaddition of 1 μL (400 μM) of the fluorescent substrate(Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂ whereMca=(7-methoxycoumarin-4-yl)-acetyl andDpa=N-3-(2,4-dinitrophenyl)-L-α-β-diaminopropionyl)) and kineticactivity was measured every minute for 20 min with excitation andemission wavelengths at 335 nm and 405 nm, respectively. Measurementswere performed in duplicate. The percent inhibition was plotted versusthe inhibitor concentration. A linear fit of the data for eachexperiment gives the IC₅₀ value of the inhibitor where y=50%.

MMP activity in the presence of H₂O₂ was evaluated with both MMP-9 andMMP-12 with 1 h of activation at concentrations close to their IC₅₀values. Using the calculated rate constants for the protected ZBGs B19and B20, it was determined that 1 h of activation time for eachproinhibitor with 100 μM H₂O₂ will provide enough 1,2-HOPO-2 or PY-2 toinhibit the MMPs at 50%. For example, for proinhibitor B17 with MMP-9,if the rate=k[B17][H₂O₂] and k=3.9 M⁻¹s⁻¹, [B17]=10 μM, and [H₂O₂]=100μM, the rate of conversion would be 3.9×10⁻⁹ M/s. Therefore, activationfor 1 h would release 14 μM 1,2-HOPO-2, or enough inhibitor to provideapproximately 50% inhibition of MMP-9 (IC₅₀ value for 1,2-HOPO-2 againstMMP-9 is ˜6 μM).

In each well, 1 μL of proinhibitors B17 and B18 and the inhibitors1,2-HOPO-2 and PY-2 in DMSO (1 mM for MMP-9 or 5 μM for MMP-12) wereincubated for 1 h at 37° C. with 10 μL H₂O₂ (1 mM in HEPES buffer, pH7.5) in MMP assay buffer for a total volume of 79 pt. A control samplecontaining 10 μL H₂O₂ (1 mM in HEPES buffer, pH 7.5) in MMP assay bufferwas also prepared to confirm that H₂O₂ did not inhibit MMP-9 or MMP-12.After activation of the proinhibitors, 20 μL of the appropriate MMP(0.45 U/mL for MMP-9 and 0.35 U/mL for MMP-12) was added and incubatedfor an additional 30 min. The reaction was initiated by the addition of1 pt (400 μM) of the fluorescent substrate and kinetic activity wasmeasured every minute for 20 min with excitation and emissionwavelengths at 335 nm and 405 nm, respectively. Enzyme activity withinhibitor was calculated with respect to the control experiment (noinhibitor present). Measurements were performed in duplicate in twoindependent experiments.

Example 9 Exemplary Oxidatively-Sensitive Prodrugs

In the development of ROS-activated proMMPi, we employed a relativelyunderutilized self-immolative protecting group with several apparentadvantages over previously described systems. The use of self-immolativelinkers has become increasingly popular in drug development, molecularsensors, and polymeric delivery systems.^(1, 19-21) Linkers that undergoself-immolative elimination upon removal of the protecting group canrelease an active species through a 1,6-benzyl elimination (FIG. 19).This reaction is thermodynamically driven by the release of CO₂ when acarbonate or carbamate ester linkage is employed.²¹⁻²³ However, in thedevelopment of proMMPi, it was found that the use of an ether linkagebetween the activating group and the inhibitor was preferred over themore commonly used carbonate ester linkage (compare compound B1 vs. B2in FIG. 19) due to better synthetic accessibility, superior hydrolyticstability, and comparably fast cleavage kinetics. Recently, this etherlinkage was utilized in studies on ROS-sensitive luciferase probes²⁴ andprotease-sensitive fluorophores.²² Nonetheless, there are essentially nostudies on the generality and utility of this promising linkingstrategy. This report investigates the scope of this ether-connected,self-immolative proinhibitor strategy with a variety of functionalgroups and MBGs.

Here we further investigate the behavior of different activationstrategies using related, but distinct self-immolative linkers forcoupling to the MBGs. All of the strategies studied here use boronicester protecting groups that can be selectively removed by H₂O₂. Aseries of methyl salicylate derivatives containing phenol, thiophenol,aniline, and benzylamine leaving groups were investigated using eitheran ether linkage, a carbonate/carbamate ester linker, or no linker tothe boronic ester protecting group (FIG. 19 and FIG. 20). In addition,we looked at a variety of MBGs protected with a boronic esterself-immolative leaving group to expand our inventory of MBGs for use innovel metalloprotein prodrugs.

Compounds B1-B3 were designed to release methyl salicylate in thepresence of H₂O₂ using a self-immolative ether linkage (B1), a carbonateester linkage (B2), or no self-immolative linker (B3) to directlycompare three possible designs of a prodrug scaffold. The syntheses ofthese compounds are described in Example 3. Compounds B1-B3 were firstexamined for activation in the presence of H₂O₂ using UV-Visspectroscopy. To a solution of the boronic ester derivative in HEPESbuffer (50 mM, pH 7.5) was added H₂O₂ and the change in absorbance wasmonitored over time. As shown in FIG. 20 for compound B1, the absorbanceover time shows an increase at 302 nm indicative of the emergence ofmethyl salicylate with a clear isobestic point at 293 nm. Similarresults were obtained with compounds B2 and B3. While compounds B1 andB2 achieved >90% cleavage within 45 min using an 18-fold excess of H₂O₂(FIG. 24-25), deprotection of compound B3 required a 180-fold excess ofH₂O₂ to realize cleavage in a comparable time frame. Release of methylsalicylate for all three compounds was confirmed by HPLC (FIG. 26-27).

The rates of conversion to methyl salicylate were determined bymonitoring the change in absorbance under pseudo first-order reactionconditions with an excess of H₂O₂. The calculated rate constants arepresented in Table 2. Consistent with earlier reports, the carbonateester derivative B2 displayed the fastest rate of conversion, but B2also underwent spontaneous hydrolytic cleavage in buffer, whereascompound B1 was stable in buffer over a 4 h period (data not shown).Introduction of the carbonate group into the self-immolative linker ofB2 leads to hydrolytic instability facilitated by nucleophilic attack ofwater at the carbonyl position which is not possible in compound B1.²⁵Interestingly, while the hydrolytic stability of B3 was comparable tothe ether linkage used in B1, the rate of conversion for B3 was abouttwo orders of magnitude slower than either B1 or B2, suggesting that useof self-immolative linker facilitates conversion to the desired activecompound.

TABLE 2 Pseudo first-order rate constants calculated with an excess ofH₂O₂. Compound k (M⁻¹s⁻¹) B1 1.12 ± 0.04 B2 2.7 ± 0.1 B3 0.031 ± 0.002B10 3.1 ± 0.5 B11 5.9 ± 0.2 B12 3.5 ± 0.3 B13 2.9 ± 0.1 B14 4.1 ± 0.2

Based on the behavior of compounds B1-B3, the most promising linkingstrategy is the benzyl ether linkage seen in compound B1. The benzylether linkage shows excellent stability in buffer while maintainingrapid cleavage kinetics upon activation. Therefore, we investigated theuse of this motif with other leaving groups. Compounds B4-B7 weresynthesized to study the effects of using sulfur (B4), aniline (B5-B6),or benzyl amine (B7) leaving groups. Evaluation with UV-Vis absorptionspectroscopy of B4-B7 in the presence of H₂O₂ showed no cleavage of theprotecting group (FIG. 29-32). Further evaluation with LC-MS showed thatthe boronic ester of compound 6 was cleaved to the phenol group, butthat the cascade reaction did not proceed as expected to release theaniline group (FIG. 33). This may reflect the general robustness ofthese amine derivatives and their ionization potential.²⁶ Compounds B8and B9 were then evaluated to investigate the use of a carbamate esterlinkage. Unlike compound B7, the carbamate self-immolative linkers in B8and B9 showed that the desired benzyl amine is released in the presenceof H₂O₂, thermodynamically driven by the release of CO₂ (FIG. 34-35).This suggests that for the release of nitrogen-derived leaving groups,the carbamate linkage may still be preferable for prodrug development.¹

To validate our observations in the context of MBGs, a series ofactivatable MBGs (prochelators)²⁷ were synthesized (compounds B10-B14,FIG. 23) and evaluated. Compounds B10 and B11 were designed with aboronic acid protecting group to improve water solubility of theprotected MBGs.¹⁵ Several other protected MBGs were examined includingthe oxygen-binding 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (B12),tropolone (B13), and 8-hydroxyquinoline (B14). Compounds B10-B14 showedrapid cleavage to the desired MBG in the presence of H₂O₂, as determinedby absorption spectroscopy (Table 2), thus confirming the broaderutility of the benzyl ether self-immolative strategy for designingmetalloprotein proinhibitors (FIG. 36-40). Additionally, use of theboronic acid derivative in B10 and B11 shows both improved solubilityand an increase in the rate of cleavage when compared to their boronicester counterparts.¹⁵ The pinacol boronic ester analog of B10 had a rateconstant of 2.9 M⁻¹s⁻¹, which is comparable to B10. However; compoundB11 showed a notable improvement in rate, increasing from 4.0 M⁻¹s⁻¹ forthe pinacol boronic ester to 5.9 M⁻¹s⁻¹ for B11. This rate approachesthat of the reported rate of 6.7 M⁻¹s⁻¹ for the carbonate ester-linkedboronic ester protected MBG.¹⁵ Compound B15 was synthesized and did notshow cleavage in the presence of H₂O₂, confirming that this protectionstrategy is not effective with nitrogen-based MBGs.²⁸ In the presence ofH₂O₂, B15 shows similar deprotection of the boronic ester to thephenolic group as B6 and B7, but does not undergo release of theprotecting group (FIG. 41). Overall, the results validate our findingsthat benzyl-ether linkages are best suited for oxygen-based MBGs.

Hydroxamic acid MBGs are the most prevalent metal chelators inmetalloprotein inhibitors, including MMPi, yet attempts to developproMMPi using hydroxamic acid MBGs have not generally been successful.²⁹Therefore, compound B16, which is comprised of phenyl hydroxamic acidprotected with the boronic-ester self-immolative linker, was synthesizedand evaluated. In the presence of H₂O₂ compound B16 showed no release ofthe desired hydroxamic acid ligand. HPLC indicates exposure to H₂O₂results in boronic ester cleavage to a phenol group, but no furthercascade reaction occurs to release the hydroxamic acid (vide supra, FIG.42).

A thorough investigation of boronic ester prochelators shows that theuse of benzyl ether self-immolative linkers provides a superior platformfor the development of metalloprotein proinhibitors with oxygen-basedleaving groups. These compounds show excellent hydrolytic stability aswell as fast rates of cleavage to the active compounds in the presenceof H₂O₂. The use of boronic acids (instead of esters) results in evenfaster cleavage and better aqueous solubility with no loss in hydroylicstability. These findings are significant in the development oftriggered metalloprotein proinhibitors, H₂O₂-activated prodrugs.

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A promising strategy in MMPi is through the development of MMP prodrugsor ‘proinhibitors’ that offer the ability to selectively controlinhibitory activity. Metalloenzyme inhibitors such as MMPi areparticularly suitable to the proinhibitor approach because suchcompounds generally contain a metal-binding group that can be blocked,which strongly attenuates their inhibitory activity. In the presence ofthe appropriate stimuli, the protecting group can be removed from themetal-binding group to release the MMPi at the site of activation, andthereby avoiding systemic inhibition of MMPs (which are necessary fornormal physiological processes).^([8,9]) However, metalloenzymeproinhibitors have not been widely investigated, especially in the caseof MMP proinhibitors. MMP proinhibitors are shown to be activated byH₂O₂ for use as protective therapeutics following ischemia andreperfusion injury during stroke (FIG. 43). As described below, theproinhibitors reported can protect the blood brain barrier (BBB) in twoways, taking advantage of both the triggering mechanism and theresulting MMPi. First, the proinhibitors will consume damaging ROS (e.g.H₂O₂), which would otherwise directly attack the BBB and also activatepathogenic MMPs. Second, the resulting active MMPi serves to inhibit anyremaining MMP activity that might damage the BBB. Thus, thisunprecedented class of proinhibitors has a dual mode of action: reducingthe amount of ROS available to activate MMPs, while also generating anactive MMPi.

Two MMPi, the pyridinone-based molecule 1,2-HOPO-2 and the pyrone-basedmolecule PY-2, were selected for this study. Both compounds are potent,semi-selective MMPi that have been previously described.^([11]) Thehydroxyl group of the zinc-binding group (ZBG) of each inhibitor wasprotected with a self-immolative protecting group containing a boronicester as the ROS-sensitive trigger (FIG. 44). In the presence of H₂O₂,the boronic ester is cleaved by nucleophilic attack of H₂O₂,facilitating a spontaneous reaction to release the active MMPi through a1,6-benzyl elimination (FIG. 43). Boronic esters as H₂O₂-reactiveprotecting groups has been well documented in the literature forH₂O₂-activated fluorophores^([12, 13]) and in the generation oftriggered Fe(III) and Cu(II) chelates.^([14, 15])

The ROS-triggered self-immolative protecting group can be attached tothe MMPi by using either an ether (B19, B20) or carbonate ester (B21)linkage at the hydroxyl group of the ZBG (FIG. 44). To determine whichlinker strategy provided the best overall approach, both the cleavagekinetics and solution stability of protected B19, B20, B21 wereexamined. The ability of these compounds to be activated by H₂O₂ wasevaluated by using electronic spectroscopy. A sample of each compound inHEPES buffer (50 mM, pH 7.5) was activated with an excess (18equiv)^([12-15]) of H₂O₂ and the change in absorbance was monitored overtime. In all cases, the spectra of the protected ZBG compounds decreasedover time while the spectra of the free ZBG appeared, demonstrating theexpected cleavage reaction. To confirm that the boronic ester moiety wasnecessary for H₂O₂ cleavage, the ZBGs were prepared with benzylprotecting groups without the boronic ester. For these compounds, nochange in absorbance was observed over time in the presence of H₂O₂.Additionally, the selectivity of the boronic ester towards H₂O₂ wasconfirmed by examining cleavage in the presence of KO₂ and catalase. Asexpected,^([12, 20]) the superoxide anion was unable to activate theprotected ZBGs.

The rates of conversion of compounds B19-B21 their respective activatedZBGs were then determined by monitoring the change in absorption usingpseudo-first order reaction conditions with an excess of H₂O₂. Thecalculated rate constants indicated that the carbonate ester linkage incompound B21 provided the fastest conversion with a rate constant of 6.7M⁻¹s⁻¹, while rate constants of 4.0 M⁻¹s⁻¹ and 2.9 M⁻¹s⁻¹ were found forcompounds B19 and B20, respectively. Upon examination of the solutionstability of these compounds, B19 and B20 were stable in buffer over a24 h time period, while B21 showed >50% hydrolysis. Although the use ofcarbonate and carbamate ester linkages in self-immolative systems aremore common (due to the additional thermodynamic driving force from therelease of CO₂ in the cascade reaction).

After establishing a strategy for the addition of H₂O₂ activatedprotecting groups to the appropriate ZBGs, the full-length inhibitors1,2-HOPO-2 and PY-2 were protected with 4-bromomethylphenyl boronic acidpinacol ester in the presence of K₂CO₃ in DMF to yield compounds B17 andB18, respectively. Activation of B17 and B18 by H₂O₂ to release1,2-HOPO-2 and PY-2 was confirmed by absorption spectroscopy. Similarspectra were obtained under the same reaction conditions as those usedfor compounds B19 and B20 indicating that the cleavage rates for theproinhibitors B17 and B18 would have comparable rate constants. The IC₅₀values of the proinhibitors B17 and B18 against MMP-9 were found to begreater than 1 mM, representing a >100 fold-increase than the activeinhibitor (FIG. 45). When B17 and B18 were tested against MMP-12, theirIC₅₀ values were found to be in the micromolar range (FIG. 25), whichwas again >100-fold less effective than their activated counterparts.Both sets of experiments show that when the ZBG of the inhibitor isprotected, the ability of the compounds to inhibit MMPs is severelyattenuated.

Having established that proinhibitors B17 and B18 could be effectivelyprotected and activated in the presence of H₂O₂, the ability of thesecompounds to inhibit MMPs after activation was evaluated. Using afluorescence-based assay, compounds B17 and B18 were tested with MMP-9and MMP-12 in the presence of H₂O₂ at concentrations close to theirreported IC₅₀ values.^([11]) MMP-9 is considered a high-value MMP targetin the context of ischemia-reperfusion injury associated withstroke.^([7]) The percent inhibition of proinhibitors B17 and B18 wereevaluated after one hour of activation with and without H₂O₂. Asexpected, when there is no hydrogen peroxide present, there is littleinhibition observed for the proinhibitors (FIG. 46). However, afteractivation with 100 μM H₂O₂, the percent inhibition observed for B17 wassimilar to that observed for the active inhibitor 1,2-HOPO-2. Assumingthat the rate constants found for the cleavage of B19 and B20 areessentially the same when incorporated into B17 and B18, then the 50%inhibition observed is consistent with the calculated amount of activeinhibitor present when exposed to 100 μM H₂O₂ for 1 h.

The proinhibitors introduced in this work demonstrate an effective meansto passivate MMPi and activate them in the presence of H₂O₂. Throughaddition of a boronic ester protecting group to the metal-binding moietyof MMPi via a self-immolative linker, proinhibitors based on twodifferent ZBGs were developed. These compounds were found to besufficiently stable in buffer and were found to have high rates ofcleavage allowing for efficient activation with H₂O₂. These compoundsshould display a dual mode of action in the prevention of reperfusioninjury, by neutralizing ROS and generating an active MMPi. To the bestof our knowledge, this is the first example of a H₂O₂ activated prodrugwhich offers a novel way to provide both spatial and temporal controlover MMP inhibition for use in reperfusion injury.

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It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A method of treating a disease in a patient in need of suchtreatment, said method comprising administering a therapeuticallyeffective amount of an oxidatively-sensitive prodrug to said patient,wherein said oxidatively-sensitive prodrug comprises a drug moietycovalently linked to an oxidatively-sensitive prodrug moiety.
 2. Themethod of claim 1, further comprising allowing saidoxidatively-sensitive prodrug to react with a reactive oxygen speciesafter administrating said oxidatively-sensitive prodrug and therebyforming a drug from said drug moiety.
 3. The method of claim 1, whereinsaid drug comprises a metal binding moiety.
 4. The method of claim 3,wherein said drug comprises a zinc binding moiety.
 5. A method ofinhibiting the activity of a metalloprotein, said method comprisingcontacting said metalloprotein with a metal binding moiety formed fromthe reaction of an oxidatively-sensitive prodrug and a reactive oxygenspecies.
 6. The method of claim 5, wherein said metalloprotein is ametalloenzyme.
 7. The method of claim 5, wherein said metalloprotein iswithin an organism.
 8. The method of claim 5, wherein saidmetalloprotein is within a reaction vessel.
 9. The method of claim 5,wherein said metalloprotein is a matrix metalloprotease.
 10. A compoundhaving the formula:

wherein, A, B, C, and D are independently a drug moiety; L¹ is a bond oran unsubstituted alkylene; X¹ is —NH— or —O; R¹ is —B(OH)₂ or anROS-reactive boronic ester; R² is independently halogen, —N(O)₂, —COOH,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, or an electron withdrawinggroup; z is an integer from 0 to
 5. 11. The compound of claim 10,comprising a metal binding moiety.
 12. The compound of claim 11, whereinsaid metal binding moiety is a zinc binding moiety.
 13. The compound ofclaim 10, wherein said ROS-reactive boronic ester is capable of reactingwith hydrogen peroxide.
 14. The compound of claim 10 of formula (I),(Ia), (III), or (IIIa), wherein A or C are independently

wherein R³ is independently halogen, —CN, —N(O)_(m), —NR⁷R⁸, —C(O)R⁹,—C(O)—OR¹⁰, —C(O)NR¹¹R¹², —OR¹³, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; m isan integer from 1 to 2; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ isindependently hydrogen, or substituted or unsubstituted alkyl; R⁵ isindependently hydrogen, or substituted or unsubstituted alkyl; a, e, andf are independently an integer from 0 to 4; b and d are independently aninteger from 0 to 3; c is an integer from 0 to 5; g is an integer from 0to 6; X¹ is —O—; and X is ═O or ═S.
 15. The compound of claim 10 offormula (II), wherein B is

wherein R³ is independently hydrogen, halogen, —CN, —N(O)_(m), —NR⁷R⁸,—C(O)R⁹, —C(O)—OR¹⁰, —C(O)NR¹¹R¹², —OR¹³, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; m is an integer from 1 to 2; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², andR¹³ are independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; h isan integer from 1 to 4; and X is ═O or ═S.
 16. The compound of claim 10of formula (III) or (Ma), wherein C is

wherein R³ is independently halogen, —CN, —N(O), —NR⁷R⁸, —C(O)R⁹,—C(O)—OR¹⁰, —C(O)NR¹¹R¹², —OR¹³, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; m isan integer from 1 to 2; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ isindependently hydrogen, or substituted or unsubstituted alkyl; X¹ is—NH—; and e is independently an integer from 0 to
 4. 17. The compound ofclaim 10 of formula (IV), wherein D is

wherein R³ is independently halogen, —CN, —N(O), —NR⁷R⁸, —C(O)R⁹,—C(O)—OR¹⁰, —C(O)NR¹¹R¹², —OR¹³, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; m isan integer from 1 to 2; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ isindependently hydrogen, or substituted or unsubstituted alkyl; R⁵ isindependently hydrogen, or substituted or unsubstituted alkyl; a, e, andf are independently an integer from 0 to 4; b and d are independently aninteger from 0 to 3; c is an integer from 0 to 5; g is an integer from 0to 6; X is ═O or ═S.
 18. A compound having the formula:

wherein E is a drug moiety; L² is independently a bond, —O—, —S—, —NH—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene; and R⁶ is asubstituted or unsubstituted carbohydrate moiety.
 19. The compound ofclaim 18, wherein E is

wherein R³ is independently halogen, —CN, —N(O)_(m), —NR⁷R⁸, —C(O)R⁹,—C(O)—OR¹⁰, —C(O)NR¹¹R¹², —OR¹³, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; m isan integer from 1 to 2; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ areindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ isindependently hydrogen, or substituted or unsubstituted alkyl; R⁵ isindependently hydrogen, or substituted or unsubstituted alkyl; a, e, andf are independently an integer from 0 to 4; b and d are independently aninteger from 0 to 3; c is an integer from 0 to 5; g is an integer from 0to 6; X is ═O or ═S.
 20. A pharmaceutical composition comprising thecompound of claim 10 and a pharmaceutically acceptable excipient.